Call for applications

APPLICATION FILE

Call for applications 2012 Certification of sites dedicated to integrated research in cancer - SIRIC -

Consortium ONCOLille Application file

Nom de l’établissement candidat

C2RC Lille CHRU & Centre Oscar Lambret

Nom du directeur du projet SIRIC

Pr. Eric Lartigau

Etablissements partenaires

CHRU of Lille Centre Oscar Lambret

Université(s) de référence

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SIRIC - CALL FOR APPLICATIONS 2012

PRES Lille Nord de France

APPLICATION FILE

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I. General presentation I.1. HISTORICAL BACKGROUND OF THE COOPERATION I.1.1.

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ONCOLILLE CONSORTIUM: A STRONG EXISTING PARTNERSHIP BETWEEN 10

ACADEMIC HOSPITALS

I.1.2.

ONCOLILLE: EUROPEAN STATE OF THE ART FACILITIES IN BASIC, TRANSLATIONAL AND CLINICAL RESEARCH IN ONCOLOGY

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ONCOLILLE: A DYNAMIC ENVIRONMENT FOR INNOVATION AND INTEGRATION

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I.2. Presentation of the partner organisation and their major assets I.3. Strategic considerations for ONCOLille

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I.1.3.

I.3.1.

A RESPONSIBILITY, A VISION AND AN AMBITION

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I.3.2.

THE RESEARCH FACILITIES

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I.3.3.

TOWARD AN INTEGRATED RESEARCH CENTRE

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I.3.4.

MANAGEMENT AND ORGANIZATION OF THE SIRIC SCIENTIFIC ISSUES

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I.3.5.

CONTRIBUTION TO THE OBJECTIVES OF THE PLAN CANCER II

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I.3.6.

INTERNATIONAL COLLABORATIONS

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I.3.7.

VALORISATION STRATEGY

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I.3.8.

DISSEMINATION STRATEGY

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I.3.9.

CONCLUSION

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II. Presentation of the medical, scientific and technological potential of the SIRIC 44 II.1. Medical activity II.1.1.

CHRU LILLE

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II.1.1.1.

ORGANIZATION OF CANCER TREATMENT AT THE CHRU

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II.1.1.2.

CANCER TREATMENT

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II.1.2.

CENTRE OSCAR LAMBRET

II.2. Research activity II.2.1.

FUNDAMENTAL SCIENCES

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49 49

II.2.1.1.

BIOLOGY

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II.2.1.2.

RESEARCH IN HUMAN AND SOCIAL SCIENCES AND PUBLIC HEALTH

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II.2.2.

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44

CLINICAL RESEARCH

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II.2.2.1.

CHRU LILLE

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II.2.2.2.

CENTRE OSCAR LAMBRET –THE CLINICAL RESEARCH UNIT

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APPLICATION FILE

II.2.3.

TRANSLATIONAL RESEARCH

II.3. Presentation of the SIRIC shared resources and facilities

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58

II.3.1.

4 INTEGRATED PLATFORMS

58

II.3.2.

INTEGRATED PLATFORM 1: BIOLOGY

59

II.3.3.

INTEGRATED PLATFORM 2: IMAGING

66

II.3.4.

INTEGRATED PLATFORM 3: ANIMAL MODELS

74

II.3.5.

INTEGRATED PLATFORM 4: CLINICAL RESEARCH AND METHODOLOGY

81

III. Integrated research programs III.1. Overview of the two integrated programs III.2. Tumour and host resistance to loco-regional treatments

91 91 93

III.2.1. MAJOR THEME OF THE PROGRAM

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III.2.1.1.

MEDICAL RATIONALE AND SCIENTIFIC OBJECTIVES OF THE PROGRAM

94

III.2.1.2.

METHODOLOGICAL BACKGROUND

95

III.2.1.3.

ASSETS OF LILLE’S TEAMS

96

III.2.1.4.

TEAMS, INSTITUTIONS AND INFRASTRUCTURES INVOLVED IN PROGRAM 1

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III.2.2. MAIN TARGETS OF THE PROGRAM’S WORK

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III.2.2.1.

BASIC RESEARCH

100

III.2.2.2.


105

III.2.2.3.

CLINICAL RESEARCH

109

III.2.2.4.

CONTRIBUTION OF HUMAN AND SOCIAL SCIENCES

114

III.2.3. EXPECTED RESULTS III.2.3.1.

IN TERMS OF PRODUCTION

III.2.3.2.

IN TERMS OF DISSEMINATION OF KNOWLEDGE AND OF PROVISIONAL CALENDAR

119 119 120

III.2.4. FOCUS ON THE EMERGING RESEARCH ASPECTS THAT MAY BENEFIT FROM FUNDING OF THE SIRIC

III.2.5. APPENDICES III.2.5.1.

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INTEGRATION WITHIN THE WHOLE SCIENTIFIC PROJECT – ARTICULATION WITH THE OTHER PROGRAMS

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III.2.5.2.

PLANNING

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III.2.5.3.

BUDGET

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III.3. Tumour dormancy and persistence III.3.1. MAJOR THEME OF THE PROGRAM

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125 126

III.3.1.1.

SCIENTIFIC OBJECTIVES OF THE PROGRAM

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III.3.1.2.

METHODOLOGICAL BACKGROUND

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III.3.1.3.

TEAMS, INSTITUTIONS AND INFRASTRUCTURES INVOLVED IN PROGRAM 2 127


APPLICATION FILE

III.3.2. MAIN TARGETS OF THE PROGRAM’S WORK

128

III.3.2.1.

BASIC RESEARCH

128

III.3.2.2.


134

III.3.2.3.

CLINICAL RESEARCH

137

III.3.3. EXPECTED RESULTS

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III.3.4. FOCUS ON THE EMERGING RESEARCH ASPECTS THAT MAY BENEFIT FROM FUNDING OF THE SIRIC

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III.3.5. APPENDICES

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III.3.5.1.

PLANNING

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III.3.5.2.

BUDGET

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IV. National and international collaborations program

142

IV.1. Role in regional and national clinical research 142 IV.2. International networks and collaborations 143 IV.3. Strategy of the SIRIC for national and international collaboration 144

V. Partnership and valorisation strategy

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V.1. Strategy and priorities V.2. Strategy implementation

146 146

V.2.1. THE TECHNOLOGY TRANSFER ORGANISATION IMPLEMENTED IN THE SCOPE OF ONCOLILLE V.2.1.1.

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THE FRAME OF THE COOPERATION WITHIN LILLE UNIVERSITY HOSPITAL AND CENTRE OSCAR LAMBRET

V.2.1.2.

146

THE FRAME OF THE COOPERATION WITH THE SATT NORD DE FRANCE VALO AND EURASANTE

147

V.2.2. KEY STRATEGIC ACTIONS

147

V.2.2.1.

TRANSFORM RESEARCH INVESTMENT INTO IP

147

V.2.2.2.

DEVELOPING AN EFFECTIVE PARTNERSHIP STRATEGY WITH INDUSTRY

147

V.2.2.3.

DEVELOPING A COMMUNICATION AND DISSEMINATION STRATEGY THAT WILL

ENHANCE

ONCOLILLE

ATTRACTIVENESS

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PROFILE:

ONCOLILLE AS A LEADING EUROPEAN ONCOLOGY RESEARCH INSTITUTE

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150

V.2.3. LINKS WITH TECHNOLOGY TRANSFER STRUCTURES (SATT)

150

V.2.4. LINKS WITH COMPETITIVENESS CLUSTERS

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VI. Knowledge and practices dissemination program VI.1. Spreading excellence, dissemination knowledge VI.2. Dissemination to the professionals VI.2.1. EXISTING DISSEMINATION PROGRAMS

152 154 154

VI.2.1.1.

ACADEMIC TEACHING

154

VI.2.1.2.

PROFESSIONAL TRAINING

154

VI.2.2. TOOLS TO BE IMPLEMENTED

155

VI.2.2.1.

DEVELOPMENT OF MASTER DEGREES

155

VI.2.2.2.

DEDICATED WEB PAGE

155

VI.2.2.3.

ONCOLILLE SCIENTIFIC SEMINARS

156

VI.3. Dissemination to the patients and the public

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VI.3.1. ACTION OF THE REGIONAL COUNCIL “THE WEEK AGAINST THE CANCER”

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VI.3.2. COMMUNICATION TO THE PATIENTS

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APPLICATION FILE

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APPLICATION FILE

Résumé du projet ONCOLille En France, l'incidence des cancers est d'environ 320 000 nouveaux cas par an. La comparaison avec les différents registres nationaux montre que la région Nord – Pas de Calais présente la plus forte incidence au niveau national, le taux de mortalité par cancer dans cette même région étant l'un des plus fort en Europe. De plus notre région, avec son passé industriel (mines, textile, sidérurgie...) présente encore de grandes disparités sociales avec un taux très élevé de chômage. Cette situation médico sociale unique a fait que les deux hôpitaux académiques de Lille, le CHRU et le Centre de Lutte contre le Cancer (CLCC Oscar Lambret) se sont unis dès 2005 afin de développer une politique médico scientifique commune dans un Groupement de Coopération Sanitaire (GCS) : le Centre Régional de Référence en Cancérologie (C2RC). Cette collaboration soutenue par le Conseil Régional, les Universités et les EPST (CNRS, INSERM...) a permis la mise en œuvre de nombreux travaux dans le champ de la recherche fondamentale, clinique et des sciences humaines et sociales. De ce fait la communauté scientifique lilloise à une très grande légitimité pour répondre à l'appel à projets Siric 2012 dans le cadre du plan cancer 2 (2009-2013). Le consortium ONCOLille regroupe des acteurs de premier plan de la recherche clinique et fondamentale (laboratoires labellisés A+ et A) avec des programmes particulièrement innovants dans les domaines de la génomique, protéomique, banque des tumeurs, modèles animaux, imagerie et méthodologie de la recherche clinique. Les chercheurs impliqués sont des leaders reconnus dans leurs domaines de compétence. Pour toutes ces raisons, ONCOLille développe un projet original en recherche intégrée sur 2 questions essentielles de la cancérologie moderne : la résistance de la tumeur et de l'hôte aux traitements loco- régionaux et la dormance/persistance tumorale après traitement. Cette recherche est base sur les compétences des acteurs de la recherche fondamentale et sur la fréquence ou l'agressivité des modèles cliniques choisis (oesophage, foie, plèvre, gynécologie, hématologie et prostate.) faisant l'objet de programmes de recherche clinique sur le site. 

Programme1 : resistance de la tumeur et de l'hôte aux traitements loco-régionaux dans les tumeurs ORL, oesophagiennes, hépatiques et gynécologiques.



Programme 2 : dormance et persistance tumorale dans les hémopathies, le mélanome et le cancer de la prostate.

Ces programmes originaux reposent sur des données provenant des travaux des équipes du site avec de potentielles retombées très importantes pour une meilleure prise en charge de nos patients. Ils intègrent des données provenant de la recherche fondamentale, de la recherche translationelle, de la recherche clinique et des sciences humaines et sociales, en particulier pour améliorer le suivi individuel et collectif des patients. La diffusion des connaissances se fera principalement en direction des médecins généralistes, de manière à produire des recommandations sur l'adaptation personnalisée du suivi et de la réinsertion professionnelle des patients. À travers une étroite collaboration avec les facultés de médecine, de pharmacie et sciences biologiques, la diffusion des connaissances se fera à travers les différents cycles de formation, et notamment les master. De nombreuses collaborations ont d‟ores et déjà été développées avec des entreprises de biotechnologie régionales et nationales à travers Eurasante. ONCOLille s‟appuie sur de nombreux partenariats existant avec des équipes de recherche fondamentale et clinique, en France (cancéropôle Nord Ouest) et à l‟international (Belgique, Hollande) : une stratégie spécifique visera à renforcer et développer de nouvelles coopérations. ONCOLille va apporter de nouvelles connaissances sur la résistance aux traitements et la persistance après traitement. L'originalité de cette démarche, totalement intégrée, regroupant toutes les facettes de la recherche en cancérologie, est d'apporter des informations essentielles en adaptation thérapeutique dans le cadre l’une médecine personnalisée. Du fait de l'incidence particulière dans notre région, ces programmes ont une indiscutable réalité clinique. Basés sur une expérience de collaboration de plus de 5 ans, regroupant tous les acteurs de la cancérologie et soutenu par les politiques régionaux, ONCOLille représente une réelle opportunité pour développer un centre de recherche intégrée sur le cancer de référence au niveau européen.

Montant demandé pour 5 ans

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7,7 Millions d’Euros

APPLICATION FILE

Summary of the ONCOLille project In France, the number of new cancer cases is approximately 320,000 yearly. In comparison with data

obtained by various departmental French cancer registries, the Nord – Pas de Calais region displays the highest rate of cancer incidence and mortality in France and one of the highest in Europe. Furthermore, the region, with its historical background of heavy industries (coal mines, steel and textile mills, etc…) is characterized by high level of unemployment, social grants and limited resources. This unique social and clinical situation spurred the two regional academic centres, the C.H.R.U. (Centre Hospitalier Régional Universitaire) and the Cancer Centre (Centre Oscar Lambret) to combine their efforts in 2005 so as to develop a common medical policy (C2RC: centre de référence regional en cancérologie) in the field of oncology. This collaboration, strongly backed by the Regional Council, has generated a large body of shared scientific research in biology, medicine and human sciences in association with the CNRS, INSERM and the Universities. As a result, our scientific and medical community is legitimate to answer and fulfil the INCa tender, within the framework of Plan Cancer 2 (2009-2013). The ONCOLille Consortium brings together outstanding strengths of researchers in basic, translational and clinical research (labelled A+ and A teams) with very successful developments (genomic, proteomic, tumour bank, animal models, imaging, methodology...). The core members of ONCOLille are recognised as international leaders in their field of competence. For all these reasons, ONCOLille develop an original project aiming to achieve state of the art integrated research in some of the most important issues for oncology: tumour resistance and persistence after loco-regional treatments. Based on a large number of clinical and fundamental research programs in aggressive diseases (oesophagus, liver, melanoma, head & neck...) or most common diseases (prostate, gynaecology, haematology…), and on the existing level of excellence, the 2 integrated programs are: 

Program 1: tumour and host resistance to loco regional treatments in the field of head and neck, oesophagus, liver and gynaecological tumours.



Program 2: tumour dormancy and persistence in the field of haematology, melanoma and prostate cancer.

They have the originality to stand on very strong basic or clinical research and to be able to achieve significant breakthroughs in the modelling of resistance to initial treatment and recurrence after treatment for the benefit of patients and healthcare providers. All programs will integrate biological research, translational research, innovative imaging, clinical research and humans sciences developments, particularly in the field of comprehensive handling of the disease for the patient and the family (global care). Dissemination of knowledge will be directed towards patients in the field of adapted follow up and professional reinsertion, as well as towards general practitioners and political authorities. Through a close collaboration with the faculty of medicine & the faculty of pharmacy and biological sciences, the most valuable results will be integrated in teaching (masters). Numerus cooperations have been already developed with local and regional biotech companies through the Eurasanté Incubator. Furthermore the existing regional (Cancéropôle Nord Ouest) and international (Belgium, Netherlands,...) cooperations will be strongly reinforced. The consortium ONCOLille will bring new data on the mechanisms of resistance and persistence to treatment in human tumours. Bringing together such information in biological models, imaging and clinical research will help to drive new studies in the field of adaptive and personalised medicine. Due to the specific cancer incidence in our region, this proposal has clinical reality. Based on the past 5 years‟ history of integrated research, together with the involvement of all players in cancer care and strong political commitment, our project provides a real opportunity to implement a truly comprehensive cancer centre in north of France.

Requested amount for 5 years

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7.700 million Euros

APPLICATION FILE

ONCOLille project I.

General presentation

I.1. HISTORICAL BACKGROUND OF THE COOPERATION I.1.1. ONCOLILLE CONSORTIUM: A STRONG EXISTING PARTNERSHIP BETWEEN ACADEMIC HOSPITALS

In France, the number of new cancer cases is approximately 320,000 yearly. When referring to data obtained by various departmental French cancer registries, the Nord – Pas de Calais region displays the highest rate of cancer incidence and mortality. In 2005, the incidence in the Nord – Pas de Calais of head and neck as well as oesophagus cancers in the male population was twice the national incidence. In such, Lille is the capital city of the region having the highest incidence and over mortality in cancer, region characterized by a high proportion of unemployment, social aids and limited resources. Most of these cancers can be considered as preventable, as they are linked to behaviour (tobacco, alcohol), environmental factors (industries), socio-economical conditions or more rarely to genetic familial factors. Local, regional and systemic recurrences are common and often associated with secondary and/or new primaries due to the same risk factors. This social and clinical reality has motivated the two academic reference oncology centres, the Centre Hospitalier Régional et Universitaire (C.H.R.U., www.chru-lille.fr) and the Centre Régional de lutte contre le Cancer (Centre Oscar Lambret, COL, www.centreoscarlambret.fr) to start a cooperation in 1999 and to sign a formal collaboration agreement in 2005 for developing a common medical policy (C2RC : centre de référence regional en cancérologie) in the field of oncology with the set up of fundamental and clinical research programs. This collaboration was developed in the framework of a large community of scientific research in biology and human sciences, strongly supported by the regional council in the fields of training and equipments. The C.H.R.U. and the COL are leading hospitals for cancer care and research: the CHRU is the largest academic hospital of France with the largest faculty of medicine ; the centre Oscar Lambret is the second cancer centre for clinical research (Details are given in chapter 2). The C2RC is developed around a medical conference including 46 physicians (23 from the CHRU and 23 from the Cancer centre). The medical programs have been integrated in between the two hospitals and are based on common or shared platforms. This organization makes the collaboration, around the patients, a clinical reality. All aspects of biological, translational and clinical research are considered in C2RC. Lille C2RC is today one of the rare fully integrated cancer patient network in France.  

ONCOLille Consortium is based on the historical collaboration of the C2RC together with new members (funding members, see 2) with scientific actions in the national framework of Plan cancer 2. A cooperation protocol is already signed in between Universities, Inserm, CNRS and the academic hospitals.

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APPLICATION FILE

In plan cancer 2, a specific emphasize has been made on social inequalities and access to care. These issues are particularly important in the social environment of Lille as stated above. Future programs and collaborations developed are in the framework of already very strong local collaborations in the public Health and Biomedical research Committee (Comité de la Recherche Biomédicale et en Santé Publique) with 4 axes:    

Cardio-vascular and metabolism Inflammation & immunology Neurosciences Cancer

The next step through SIRIC is to secure this organization and develop new research programs oriented to Human Sciences, biology, clinical research and the production of recommendation for patients care

I.1.2. ONCOLILLE: EUROPEAN STATE OF THE ART FACILITIES IN BASIC, TRANSLATIONAL AND CLINICAL RESEARCH IN ONCOLOGY

One of the success factors in the C2RC has been the mutualisation of expertise to be successful at national levels as for:   

multidisciplinary meetings for treatment decision working with physicians from the 2 hospitals platforms (see above), education and training.

This has been particularly demonstrated in some pilot activities like: Cancer registry of Lille and its region: the cancer registry is integrated in the C2RC from January 1st 2009. The data are collected from 35 sources (pathology, DIM, health authorities, private centres, biology laboratories…). In 5881 cases have been validated and results published (www.registrecancers59.fr).  Common tool for the analysis of oncology activity – OncoDIM: since 2001, the professionals of the two “Départements d‟information médicale” have developed a common tool to analyse and describe the activity in oncology of the two hospitals and of the other regional hospitals or clinics. This action has been strongly supported by the regional health authority (ARH-ARS) and by the Regional Council.  Pilot clinical programs: 

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Aging: a pilot unit has been developed and is labelled by the INCa. Paediatrics: onco-haematology is treated in the CHRU and solid tumours at the COL. The two Departments are reference centres and are the coordinators of the regional multidisciplinary clinic. Bone metastases and sarcomas: due to the requested multidisciplinary approach (surgery, pathology, medical and radiation oncology, these two clinical situations have been totally integrated by the C2RC. The sarcoma clinic is labelled by INCa.

ONCOLille brings already together many platforms in the field of research and care, as for example a tumour bank (labelled by INCa with more than 100, 000 specimen) or robotic equipments (Robotic surgery with a Da Vinci Surgical robot, CyberKnife implemented in 2007 after a successful answer to a National cancer Institute national tender with more than 1000 patients treated).

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APPLICATION FILE

 Clinical research Clinical research programs are shared in between the two hospitals. More than 250 trials are continuously ongoing. The integrated clinical research unit from the COL and the Clinical Investigation Centre (CIC/Inserm) from the CHRU have signed a cooperation agreement in 2009.

 Training Within the framework of the largest medical school in France, the C2RC training policy allows the organization of many educational and training programs. For example:    

Yearly « Régionales de Cancérologie » workshop Regional oncology network Education of clinical research technicians Training of medical students and internes …

I.1.3. ONCOLILLE: A DYNAMIC ENVIRONMENT FOR INNOVATION AND INTEGRATION This collaboration, strongly backed by the Regional Council with grants for equipments and training programs, has generated a large body of shared scientific research in human sciences, biology and medicine. In association with the CNRS, INSERM, University.... ONCOLille gathers outstanding strengths researchers in basic, translational and clinical research (several A+ and A team or researchers). The interactions have been made possible by the geography with all teams located on the medical campus (13 000 employees) and close to the Universities and associated research campus (Pasteur, IBL...).

GEOGRAPHICAL Situation of the Partners

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APPLICATION FILE

The specificity of the cancer incidence made the cooperation a necessity and a reality in order to be able to tackle the enormous challenge of taking care of our patients in all aspects: research, treatment and socio professional reinsertion. A very good example is our tumour bank which, in 2009, recieved the highest national ranking for scientific contributions .

As a result, our medical and scientific community is now particularly suited to answer and fulfil the INCa tender, our project complying totally with the framework of Plan Cancer 2 (2009-2013). All the partners are strongly convinced of our legitimacy to become a SIRIC. The funding members are listed below. Based on the past 5 years‟ history of integrated research, together with the involvement of all players in cancer care and strong political commitment, our project provides a real opportunity to implement a truly comprehensive cancer centre in the North of France.

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APPLICATION FILE

I.2. Presentation of the partner organisation and their major assets

CHRU Management

M Yvonnick MORICE, General Manager of the CHRU de Lille Contact  Ms Floriane BOUGEARD, Manager of the Federation of Oncology  2, avenue Oscar Lambret – 59 037 Lille Cedex  00 33 3 20 44 59 62

Key figures / Key features The Centre Hospitalier Regional Universitaire of Lille (CHRU) is a public institution and the only University Hospital of the Nord-Pas de Calais area (4 million inhabitants – 7% of the french population). It is the regional reference platform for most medical, surgical and technical activities. The campus of the University Hospital is vast and includes on one single location: 12 specialized hospitals, 3 universities (Medicine, Dental and Pharmacy). The Centre Oscar Lambret, dedicated to cancer treatment, is located nearby, which ensures close links between them. Key figures:  2 965 beds  13,500 employees (including 3000 physicians)  Receive 120,000 Emergencies each year  Yearly 93 483 in-patients and 1,192 290 outpatient  Annual budget : 950 millions € The CHRU dispose of many assets, including the latest and most advanced equipments such as platforms in imaging (6 MRI’s including 1 dedicated to research, 12 CT scans, 7 digital angiographies, 7 gamma cameras, 1 TEP), surgical facilities ( 80 OR, 16 surgical lasers, 1 Stereotactic radio-surgery Gamma-Knife ®…) and a biologypathology Centre including 23 laboratories providing modern diagnosis technologies.

Team involved in ONCOLille Laboratory of cellular haematology, Dermatology hospital, Urology service, Gynecology department, Head and neck cancer department, Medical oncology department, Department of digestive and oncological surgery, Gastroenterology and hepathology department, General and Digestive surgery, Pneumology and chest oncology, EA 2694 (Health economy), Clinical research unit, Institute of Pathology, Centre of BiologyPathology, Inserm U703, Imaging Department, Service of Urological, Head and Neck and Hematological Radiology, Environment and professional pathologies department, CRDPD EA, Geriatrics department

Description (skills & resources) The coordination of the oncology activities is ensured by the "Federation of Oncology ", which constitutes an internal network support, promoting a multidisciplinary yet integrated care for the diagnosis and treatment of cancer patients. The Federation promotes patient support and encourages the emergence of innovative activities and scientific projects in the field of malignancies, and in particular the collaborations with Northwest Cancéropôle fundamental research units and laboratories. The Federation of Oncology from CHRU participates, in connection with the Faculty of medicine - including its continuous medical education Department and Centre Oscar Lambret - to theoretical and practical teaching as well as continuing education for physicians, medical students and staff.

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APPLICATION FILE

Main assets for ONCOLille The CHRU de Lille is the first institution within the north west interregion for cancer patients with 9 976 inpatients hospitalized in 2010 (95% of adults and 5% of children). Among them 70 to 75% are new patients. Cancer patients represent 16.2% of hospital stays of the CHRU corresponding to 29 251 stays in year 2010. th

rd

The CHRU de Lille is the 4 university hospital in France in terms of scientific publications, the 3 in clinical research : a) On the period 2006-2010, the scientific publications in haematology realized by the establishment represented 10% of the publications written in France in this field, but 14.4% of the citations. In oncology, 3.7% of the publications and 5.7% of the citations (Data issued from Incites/Web of Science – Thomson Reuters). Haematology and oncology are, in terms of citations, the first and third disciplines :

b) Number of trials and number of included patients: each year, the CHRU de Lille sponsors nearly 70 new studies and is investigator centre in nearly 900 studies (academic and industrial). In 2010, more than 4000 patients have been included in clinical trials. The participation of patients with cancer to clinical trials has increased of 40% between 2009 and 2010, reaching 1113 patients in 2010 for 322 active clinical trials both academic and pharmaceutical companies driven. Oncology represents nearly 20% of research activities and is one of the 4 main axis of research of the establishment. CHRU of Lille will support and participate in SIRIC project, through research teams, technological equipment and active file of patients.

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APPLICATION FILE

Centre Oscar Lambret Management

Bernard Leclercq, General Director Contact  Tel: +33 (0)3 20 29 59 59  3 rue F. Combemale, 59000 Lille  http://www. centreoscarlambret.fr

Key figures / Key features The Centre Oscar Lambret (COL) is the cancer centre of the Nord Pas de Calais area. The COL is member of Unicancer group as well the 17 others cancer centres in France. The 3 missions of the institution are: care, teaching and research. Values are: multidisciplinarity, development of medical progress through research and innovation and optimal care to the patient and his family. Key figures:  780 employees  210 beds and places  Every year: 16 000 patients treated, 37 000 days in-hospital, 45 000 medical consultations, more than 50 000 radiotherapy fractions and 10 000 chemotherapy in out patient hospital.  Annual budget: 78 millions € More than 1800 patients are treated annually for breast cancer, 900 patients for head and neck cancer, 500 patients for gynecological cancer, 500 patients for digestive cancer, 350 patients for lung cancer, 300 patients for urological cancer, 200 patients for soft tissue sarcoma and about 120 patients with pediatric cancer. The institution has a large and innovative technical support: a surgical robot (Da Vinci), a platform of imaging including 1 IRM 3T, TEP scan, 2 gamma cameras, 3 ultrasound, one mammotome), a large radiotherapy platform (2 varian Clinac, 1 Primus Siemens, 2 tomotherapy, 1 Cyberknife) and brachytherapy equipment (1 HDR and 3 PDR).

Team involved in ONCOLille Digestive and Urology department, Head and neck cancer department, Pneumology,chest and sarcoma departement, Radiotherapy department, U837 (cellular and molecular targeting for cancer treatment), Clinical research unit, Methodology and Biostatistic Unit and the platform of Biology-Pathology

Description (skills & resources) The coordination of the oncology activities is ensured by the 3C promoting a multidisciplinary integrated care for the diagnosis and treatment of cancer patients. It participates with the Federation of Oncology from the CHRU, in connection with the Faculty of medicine to theoretical and practical teaching as well as continuing education for physicians, medical students and staff.

Main assets for ONCOLille The COL is the third CLCC in term of clinical research with more than 700 patients included in clinical trials (13% of the active file of patients). In 2010, 158 phase 1 to 3 clinical trials have been activated with 66% of academic studies. 19 PHRC (Programme hospitalier de recherche Clinique) have been funded and sponsored by the COL since 2003.

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APPLICATION FILE

Centre de Référence Régional en Cancérologie (CRRC) Management

Françoise Weingertner – Director Contact  Tel: +33 (0)3 XX 20 44 47 40XX XX XX  2, avenue Oscar Lambret – 59 037 Lille Cedex  http://www. http://www.centreoscarlambret.fr/accueil/menumilieu/le-centre-oscar-lambret/centre-regional-de-reference-encancerologie.html

Key figures / Key features The Health-care cooperation group « Centre de Référence Régional en Cancérologie » (C2RC for regional reference centre in oncology) was created by CHRU of Lille and the Centre de Lutte Contre le Cancer, Oscar Lambret (COL). The objective of the cooperation is the preparation and the implementation of a common medical and scientific project in oncology. Focused on innovation, the first medical and scientific project allowed implementing innovative techniques and procedures of medical care.

Team involved in ONCOLille CHRU: Laboratory of cellular hematology, Dermatology hospital, Urology service, Gynecology department, Head and neck cancer department, Medical oncology department, Department of digestive and oncological surgery, Gastroenterology and hepathology department, General and Digestive surgery, Pneumology and chest oncology, EA 2694 (Health economy), Clinical research unit, Institute of Pathology, Centre of Biology-Pathology, Inserm U703, Imaging Department, Service of Urological, Head and Neck and Hematological Radiology, Environment and professional pathologies department, CRDPD EA, Geriatrics department COL: Urology and digestive oncology department, Head and neck cancer department, Methodology and biostatistic unit, Clinical research unit, Laboratory of Human Molecular Oncology, Service

Description (skills & resources) Lille site acquired, through this strenghtened cooperation, hightech equipments like the Gamma-knife, the Cyber-knife, a surgical robot or a laser ureteroscope. The group manages also the tumor library, the regional centre of molecular pathology and the platform of molecular biology which benefit from the INCa support. The activity of molecular biology is interregional and for many tests national and international. To ensure sustainable development, the C2RC invested in high-rate sequencing. Medical teams of COL and CHRU collaborate in the framework of the C2RC to implement coordinated and multidisciplinary actions. For instance, the medical care of sarcoma, bone or brain metastasis, oncopediatry and ongeriatry are managed in the context of medical competence sharing.

Main assets for ONCOLille C2RC engaged in 2011 a process of actualisation of its medical and scientific project. One of the main axes is the research: CHRU and COL activities represent a critical mass and a high-powered element for research development. The project is especially suitable for a site strategy in which both institutions would benefit from this in terms of lisibility and attractivity. Elsewhere, the project will integrate the notion of continuum between basic research and clinical research. The organization is the key of the project: single window, common scientific commitee, standardisation of procedures, ressource pooling, research professionalisation improved by medical and non medical training programs linked to the universitiies…The system that C2RC will implement in 2012 will support the SIRIC ONCOLille project through solid partnerships of the local actors to the benefit of research.

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Lille Institute of Biology Management

Pr Y. De Launoit- Director Contact  Tel: +33 (0)3 20 87 10 00  1, rue du professeur Calmette, BP 447, 59021 Lille, France  http://www.ibl.fr/

Key figures / Key features In 1996, the "Centre National de la Recherche Scientifique" (CNRS), the French national organization for scientific research, with strong support of national and regional authorities, created the "Institut de Biologie de Lille” (IBL) located on campus of the Institut Pasteur de Lille. The IBL research centre was founded to reinforce basic biology science in the Institut Pasteur de Lille in the Nord-Pas de Calais region by, for example, welcoming group leaders and permitting them to develop highly competitive research. Research programs were initially conducted in the fields of human genetic, cellular biology, cancer, microbiology and biomolecule chemistry. IBL covers a total of 12,000 square meters with about 250 people: Senior scientists, post-docs, PhD and master students, research assistants and technicians. It includes 3 mixt research units (UMR 8161, UMR 8199 and UMR 8204) containing:     

55 researchers 118 scientific, technic and administrative staff 13 postdoctorants 44 students 1 start up

In particular, UMR 8161 which is involved in SIRIC programs is composed of:      

20 researchers 24 scientific staff 20 technic and administrative staff 3 postdoc 12 PhD students 4 students

Team involved in ONCOLille      

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Team 1: Cancer Biology and Chemistry (Oleg Melnyk). Team 2: Functional Analyses of the tumour suppressor gene HIC1 (Dominique Leprince) Team 3: VE-statin/egfl7 and vascular development (Fabrice Soncin). Team 4: Initiation of epithelial cancers (Corinne Abbadie). Team 5: Virus-Cancer-Transcription (Yvan de Launoit). Team 6: Signalisation, Apoptosis and Cancer (David Tulasne).


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Description (skills & resources)  The participation of recognized teams in basic research in oncology (more than 200 peer-reviewed scientific publications between 2006 and 2011, including 12 in journals of IF≥ 10)  An administrative unit takes in charge the administrative, human resources, financial, technical and computing network management.  The pooling of resources allowing the creation of technology platforms  The creation of inter-disciplinary research programs (chemistry/biology and clinical research/basic research)  An active scientific policy to strengthen the links between existing teams and to support emerging groups with monstly seminars in the course of which teams present their works and one yearly meeting.  Industrial partnerships with the accompaniment of the start-up Innobioships  A program of scientific activities with national and international seminars aimed at the scientific community and the journal club aimed at post-docs, PhD students and trainees.

Main assets for ONCOLille A strong scientific activity in the field of oncology with various subjects:  Associated cancers to Hepatitis C Virus and Epstein-Barr virus (hepatocarcinomas, Hodgkin’s lymphoma (HL), nasopharyngeal carcinomas (NPC) and peripheral T/NK-cell lymphomas.  Gene control by Erg protein in skeletal development and bone metastases in prostate cancer.  Molecular mechanisms involved in the initiation of epithelial cell transformation (escape from programmed cell death that could favour the initial emergence of transformed cells as well as their survival and growth in the tumour).  The tyrosine kinase receptor MET and its ligand hepatocyte growth factor/ scatter factor (HGF/SF) and the deregulation of its signalling during tumours through different approaches (signal transduction of MET, design of novel cancer strategies targeting the MET tyrosine kinase receptor, proteolytic processing of the Met receptor and transcriptional regulation induced by ligand-activated Met in development and tumourigenesis.  The VE-statin/egfl7 gene which is specifically expressed in endothelial cells: functions and expression during embryonic development and in various pathological conditions. Several integrated platforms will be a strong support for development of SIRIC programs:  A tumour model platform with for objective is to provide animal models (Mouse Embryo development and Transgenic Models) and mostly cancer models (Tumour graft, Tumour growth evaluation, Metastases development and evaluation)  The MICPaL platform with 4 technical trays (photonic microscopy, electronic microscopy, atomic force microscopy and cytometry).  The Peptide CSB platform “Peptide Chemistry Systems Biology”  The innovating start-up “Innobioships” which offers ways to unravel biomolecular interactions between proteins, antibodies, antigens, receptors, ligands, cells, low-molecular-weight compounds, nutraceuticals and so on.

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Institut de Recherche sur le Cancer de Lille (IRCL) Management

Pr Jean Krembel – Director Contact

Tel: +33 (0)3 20 12 92 20 Place de Verdun 59045 Lille Cedex http://ircl.org/ Key figures / Key features The Franco-American Foundation recognized of public utility, referred to as the "Institute for research on cancer of Lille", was established in 1936 as an independent centre of “fundamental research on cancer”. Located in the close vicinity of the Faculty of medicine, CHRU and Centre Oscar Lambret, IRCL played a key role in the development of both basic and clinical cancer research in Lille. Its scientific activity, initially dedicated to biochemical and biochemical approaches, focused during the last two decades on cancer genomics, cancer cell biology and anticancer drugs. IRCL covers a total of 2,500 square meters and hosts about 70 people: senior scientists, clinicians, post-docs, PhD and master students, research assistants, technicians and administrative staff. IRCL hosts:  3 research teams belonging to the Inserm U387/JPARC unit (Jean-Pierre Aubert Centre)  the administration of the Institute of Predictive Medicine and Therapeutic Research (IMPRT, scientific director: Régis Bordet, administrative director: Maud Collyn)  two integrated platforms: the Functional Genomics Platform (IMPRT, University of Lille2 and IRCL - director: Martin Figeac - IBiSA and EQUIPEX label) and the Cytometry and Cell Sorting Platform (IMPRT - director: Nathalie Jouy - IBiSA label)  TuDor Biotech, a start-up created by a researcher from one of the JPARC teams

Team involved in ONCOLille  Team 3: Factors of persistence of leukemic cells (Bruno QUESNEL)  Team 4: Molecular and cellular targeting for the treatment of the cancer (Pierre FORMSTECHER)

Description (skills & resources)  The participation of recognized teams in basic and clinical research in oncology (86 peer-reviewed scientific publications in journals of IF>5 between 2006 and 2011, including 30 in journals of IF>10, like NEJM, JCO, JNCI and Blood)  Organization of scientific meetings and seminars to strength the links between teams  An administrative unit takes in charge human resources and financial management.  IRCL hosts the common warehouse of the Jean-Pierre Aubert Research Centre, providing biological reagents and cell culture vessels to all teams. A specific mission of IRCL administration is to stimulate and collect donations from givers. For this purpose, IRCL has an active communication policy targeting regional media (newspapers and TV networks), organizes various events open to the public and develops specific contacts with lawyers and notaries to encourage donations (inheritance).

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Main assets for ONCOLille  By providing a stimulating scientific environment for clinical researchers, laboratory surfaces for academic research teams and key technological platforms, IRCL, ideally located next to CHRU and COL, plays a pivotal role in the development of translational cancer research on the Lille University medical campus  A strategic contribution of IRCL is its ability to mobilize money in a very flexible and reactive manner to support emerging projects, hire post-docs and technicians and accelerate technological evolution, by giving starting support for buying new equipments.  By supporting and accelerating the development of an outstanding functional genomics facility dedicated to cancer research, IRCL gives a selective advantage to its research teams, leading to outstanding scientific contributions in the field of the molecular characterization of leukaemias.  Being a foundation, IRCL can mobilize private money. It is the only foundation dedicated to cancer research in the North of France.

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Institut Pasteur de Lille Management

Pr Jacques Richir- Director Contact  Tel: +33 (0)3 20 87 78 00  1 r Prof Calmette 59000 LILLE  http://www.pasteur-lille.fr/

Key figures / Key features The Institut Pasteur de Lille is a private non-profit foundation whose mission is to contribute to the prevention and treatment of diseases through research, training and public health actions. Research and prevention have always been closely linked. At the origin of the development of the BCG vaccine (Bacille Calmette et Guérin), the Institut Pasteur de Lille employs today more than 400 people working every day to bring improvement in the health domain. Internationally recognized medical teams conduct research on the major diseases: cancer; diabetes; obesity; neurodegenerative diseases, such as Alzheimer's disease; infectious diseases such as tuberculosis and parasitic diseases such as malaria.

Team involved in ONCOLille Y DeLaunoit, J Vicogne, V Fafeur, E Adriaenssens, F Soncin, D Tulasne, O Melnyk, N Delhem, M Duterque, R Bourette

Description (skills & resources) In addition to research activities, the Institut Pasteur de Lille is a training centre, an international vaccination centre approved by the World Health Organization and a compelling actor of regional public health: a reference on all questions about nutrition and the largest centre of health examination to the North of Paris. The Institute also offers health workshops on food, memory or conditioning to physical effort and consultations to stop smoking, better manage its consumption of alcohol or take stock of his physical activity. The Institut Pasteur de Lille Lille hosts several high level Research Units:  INFECTION AND IMMUNITY with the Centre d'Infection et d'Immunité de Lille [CIIL] (Director: Camille LOCHT)  CANCER with the Institut de Biologie de Lille (Director : Yvan de LAUNOIT) and the Laboratory of Toxicology (Daniel MARZIN) CARDIOVASCULAR, METABOLIC AND NEURODEGENERATIVE DISEASES (with 3 teams : Public Health and Molecular Epidemiology of Aging-Related Diseases (Philippe AMOUYEL); Genomics and Metabolic Diseases (Philippe FROGUEL); Nuclear Receptors, Cardiovascular Diseases and Diabetes (Bart STAELS)  CROSS-SECTIONAL AND EMERGING with 4 teams: Biostructures and Molecular Drug Discovery (Benoît DÉPREZ); Inhibition of Nonsense-Mediated mRNA Decay (Fabrice LEJEUNE); Microbiological Safety Unit (Michèle VIALETTE)

Main assets for ONCOLille The Institut Pasteur groups a series of technological platforms accessible to researchers of the centre: Pletysmography / Functional Investigation of Airway Diseases, Microscopy - Imaging - Cytometry of the Pasteur Lille Campus (MICPaL) Facility, Surface Plasmon Resonance Platform, Transcriptomics and Applied Genomics Group (TAG), Nuclear Magnetic Resonance, Animal Unit, High Security Laboratory, Genomic Analysis Laboratory, High Throughput Genomic Platform (Genoscreen). The Institut Pasteur will put at disposal of ONCOLille its infrastructures and resources.

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Lille 2 University “Law and Health” Pr Christian Sergheraert – President Contact  Tel: +33 (0)3 20 96 43 43  42, rue Paul Duez 59000 LILLE  http://www.univ-lille2.fr/

Key figures / Key features Lille 2 University “Law and Health” is part of the leading European universities. Associated with major national research organizations, the University has world-class laboratories and researchers. Lille 2 University offers a full range of training and career opportunities in 4 major poles: Law, Health, Management and Sport, which do the reputation of the University. Key figures          

27, 682 students in 2008/2009 90 Student associations 1198 teachers and teacher-researchers 924 engineers, administrative and technical staff 51 laboratories and research teams linked to Inserm, CNRS More than 200 national diplomas More than 200 university degrees 17 sites spread over 188 549 m² of built area 4 academic libraries and various partners documentation centres 139,6 millions of Euros of consolidated budget.

Team involved in ONCOLille Y DeLaunoit, J Vicogne, V Fafeur, E Adriaenssens, F Soncin, D Tulasne, O Melnyk, N Delhem, M Duterque, R Bourette, B Quesnel, P Formstecher, A Lansiaux, R Polakowska, I Vanseuningen, M Cheok, N Porchet, C Preudhomme, JF Gossens, R Millet, P Chavatte, JP Peyrat, MC Copin, JL Lefebvre, D Chevalier, M Hebbar, E Lartigau, JP Triboulet, C Mariette, N Penel, S Fantoni, P Frimat, D Huglo, S Mordon, L Mortier, L Lemaitre, P Puech, A Villiers, N Reynaert, T Alam, F Briatte, A Maucourant, A Duhamel

Description (skills & resources) A High-level scientific research pole:

Research is a critical mission of the University, strongly associated with large organizations such as the Centre National de Recherche Scientifique (CNRS) and the National Institute of health and medical research (Inserm), and in close partnership in the field of health, with clinical research. Privileged partner of the CHRU, it has a pole of research projects common to both institutions. Below is described the means of Lille 2 to develop research projects:  51 research teams gather 1200 teachers and teacher-researchers and 924 personnel involved in research. Among them, teachers-researchers share their time between teaching and research or clinical activities.  2 doctoral schools: one in the field of legal, political, economic and management sciences, the other in biologyhealth.  4 major areas of research : Life and Heath sciences, Legal, political and social sciences, Sciences of Management, Sciences of Sports  2 federal research institutes: IFR 114 (Predictive Medicine and therapeutic Research Institute) and IFR 142 (Molecular and cellular medicine)

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 3 research centres: - Centre Jean-Pierre Aubert dedicated to the fight against cancer and to neurosciences (Inserm U 837: centre mixte de recherche Université Lille 2 - Inserm) ; - Centre d’Infection et d’Immunité de Lille (Inserm U 1019 - CNRS UMR 8204: centre mixte de recherche Université Lille 2 - Inserm - CNRS - Institut Pasteur de Lille - Université Lille 1) ; - Centre de recherches Droits et perspectives du droit (EA 4447) Lille2 is deeply involved in the SIRICprograms since it hosts numerous research teams of the SIRIC in particular in the scientific and clinical programs “dormance” and “resistance”, in the biology platform and SHS projects (especially those concerning health law).

Main assets for ONCOLille Lille 2 University develops themes of research of excellence and especially in the field of cancer with in close collaboration with theCancéropôle Nord-Ouest and Génopole de Lille. Many technical platforms come in support of this advanced research:  Structural and functional genomics: a platform dedicated to genome analyses and certified by IBiSA. The platform is deeply committed to cancer research projects and has been involved in many high level publications in the field.  A high-tech animal facility : In the field of cancer, several groups are setting up a number of projects (U387, team 3, Bruno Quesnel, U387, team 4, Pierre Formstecher, U837, team 5, Isabelle Van Seuningen).  Animal imaging models dedicated to the investigation of large animal models  Imaging capacities : including the Nuclear Medicine Departments and Radiology Departments. The main objectives of these groups are to identify the best imaging markers for early diagnosis of cancer and to identify specific tools for post-treatment follow-up.  Biotherapy platform  The CRRC Tumour Molecular Biology Platform, setting up to carry out newly-developed molecular tests as part of the care of cancer patients in the region.  The Regional Cancer Reference Centre (C2RC) tumour bank with teams from the CHRU (Anatomical pathology department and haematology laboratory) and from the COL (Anatomical pathology department) with a high level scientific production (in 2009, 11 publications for Cell library and 7 publications for tissue library).

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Lille 1 University “Sciences and Technology” Philippe Rollet- President Contact  Tel: +33 (0)3 20 43 43 43  Cité scientifique 59655 Villeneuve d’Ascq Cedex  http://www.univ-lille1.fr/

Key figures / Key features Lille1 University is a multidisciplinary University: Science and technology, engineering, human and social sciences, economics and management. It draws its strength from its great research potential such as evidenced by assessments and international rankings and close collaboration with research organizations with 18,000 students and open collaborations with the economic and social world. Key figures         

18, 000 students of which 20 % of international students 10, 000 Auditors in continuing education 1, 500 Teacher-Researchers, teachers of the second degree 162 CNRS Researchers 900 AITOS (Administrative, engineers, technicians and service workers) 40 library posts 153 ITA (CNRS, engineers, technicians and Administrative staff) 80 millions of Euros for budget (pay off) A domain of 110 ha and implantations to Lille (IAE), Sallaumines, Tourcoing, Wimereux (Marin Station)

Team involved in ONCOLille H Hondermarck, X LeBourhis, JF Bodart, T Lefebvre, N Prevarskaya, I Fournier, M Salzet, Y DeLaunoit, J Vicogne, V Fafeur, E Adriaenssens, F Soncin, D Tulasne, O Melnyk, N Delhem, M Duterque, R Bourette

Description (skills & resources) Lille1University is one of the three universities of the Lille metropolis. It delivers more than 160 national diplomas in the field of sciences and technology. It is a member of the Lille University (pole de recherché et d’enseignement supérieur PRES). Lille 1 university is divided in several Training and research faculty units = UFR : Biology, Chemistry, Geography and Planning, Computer electronics Electrotechnics automatics (IEEA), Mathematics, Physics, Earth Sciences, Economic and social Sciences The UFR of Biology that covers the fields of biochemistry, cellular biology, microbiology, animal physiology and vegetal physiology:  provides a scientific, cultural and professional training in the field of biology  enhances the professional insertion of students coming from its training  participates to actions of in-service education  is a meeting point between trainings, structures (lab and technical trays) and the socioeconomic world. It is also a high-level basic and applied research produced by:  11 research labs (with 5 labelled CNRS, INSERM or INRA) federated within 2 Institutes : - l'Institut de Recherche Pluridisciplinaire en Biologie et Biotechnologie (IRPBB / IFR 147) - l’Institut Pluridisciplinaire de Recherche en Sciences de l'Environnement (IREPSE)

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 1 attached Institute (Institut de Recherche Interdisciplinaire / IRI)  3 common centres and technological trays (cell imaging, animal facilities)  1 marine station It is also a managment unit with central services that allow users to work in good conditions and in synergy.

Main assets for ONCOLille Lille 1 university hosts several basic research teams of the SIRIC of which Inserm and CNRS units that are directly involved in scientific programs or in the Biology platform. Moreover, an IBIsA labellized Proteomic and glycobiology platform is well-operational with a.common centre of mass spectrometry, a tray of proteomic Hi_Prot, a tray of glycotechnologies, a plasmonic Surface resonance tray, a RMN and tray of structural glycobiology and a MALDI Tof Imaging.

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Lille 3 University “Sciences and Technology” Jean Claude Dupas- Président Contact  Pr Véronique Christophe  Domaine Universitaire du Pont de Bois, BP 60149, 59653 Villeneuve d'Ascq Cedex  Email. [email protected]  http://www.univ-lille3.fr/

Key figures / Key features Lille 3 University welcomes each year more than 18,000 students, including 1400 students from 107 countries, and employs nearly 1500 permanent staff. Its research activity and its training offer cover three main areas: Humanities, human and social sciences, economics and management. Founding member of the "PRES Université Lille Nord de France", Lille 3 University is engaged in an ambitious approach to increase its reach and its attractiveness, stating its place in the regional landscape and on the international scene. The University combines the scientific requirement, pedagogical support focused on the success and new digital practices and an international outreach through scientific networks.

Team involved in ONCOLille  EQUIPPE; EA 4018: Economie Quantitative Intégration Politiques Publiques Econométrie (Economy Quantitative Integration Public Policy Econometrics). Grade A J FONCEL, S DABO, O TORRES  URECA EA 1059: Unité de Recherche en sciences Cognitives et Affectives (Unit Research on Affectives and Cognitives Sciences). Grade A, V CHRISTOPHE, P ANTOINE, JL NANDRINO, E FOURNIER  GERiiCCO EA 4073: Groupe d’Etudes et de Recherche Interdisciplinaire en Information et en Communication (Interdisciplinary Research and Study Group in Information and Communication). Grade B A LAMY, G BLANCHARD, S CHAUDIRON

Description (skills & resources) QUALITY TRAINING FOCUSED ON THE SUCCESS AND RESEARCH Training offer is available in 32 license and master options. It revolves around 14 units for training and research and 2 institutes (IUT for Technological University Institute and Training institute for musicians). The University delivers more than 160 national degrees per year. Teachings are transdisciplinary and relied on the latest research, on a rich documentary potential (800,000 volumes), on high-performance equipment (visio Conference, resource centre for language, resource centre for coaching in training, etc.) and accessible digital services (University Digital "wireless", digital work environment, etc.). A POLE OF REFERENCE FOR RESEARCH IN HUMANITIES AND SOCIAL SCIENCES Lille 3 University tends to become a pole of reference in Humanities and social sciences. It promotes a multidisciplinary research and cooperation policy with basic sciences. At Lille 3, research is organized around 14 laboratories, of which 4 joint research units attached to the CNRS. Workforce highlights the importance of scientific capacity: 147 professors of universities and assimilated and 370 assistant professors. In 2009, the quality of research units has been underscored by AERES; 12 of them (on the 16 then existing) have noted A or A +. The University strengthens its research activities particularly in behavioural and cognitive psychology, information and communication sciences, language, education and sociology centred on the individual sciences. Since 10 years, the University progressively structured an engineering project and valorisation service which

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supports collaborations with the socio-economic world and diffuses into society the laboratory skills. In 2008, 3 laboratories thus obtained the label “Resource Centre for scientific and technological expertise (CREST)” for their ability to technology transfer. Lille 3 has to this day many contracts, including 16 contracts with the national research agency and 4 European projects. Doctoral training to Lille 3 is embarked on an ambitious will of full integration of doctoral students in the international scientific community. It is divided into 3 doctoral schools, members of the College doctoral of Lille Nord de France: ED Sciences of man and society (SHS) of which Lille 3 is the carrier, the ED economic Sciences, social, development and management sciences (SESAM), ED Sciences for the engineer (SPI). With 683 PhDs, ED SHS is one of two larger doctoral schools of the region in terms of personnel. It was assessed A by AERES in 2009. The University brings the MESHS (European House of Human and Society sciences), a service and research unit in partnership with CNRS to structure the regional interdisciplinary research. The laboratories participate indeed to opened programs with exact sciences research units. This opening is largely supported by the university that dedicates one third of its budget to these federative projects including projects relative to Health (cancer, alzheimer, patient and family caring, rehabilitation…).

Main assets for ONCOLille Lille 3 University hosts 3 SIRIC laboratories which develop transversal projects with the field of health and more particularly in cancer with:  Information and communication sciences (GERIICO lab – Interdisciplinary study and research group in information and communication)  Econometry (EQUIPPE lab – quantitative economy integration public policy econometry)  Human sciences (URECA lab – research unit on affective and cognitive sciences) Lille3 give to SIRIC teams the innovating technological M-PACE platform (platform for measuring behaviour in the areas of perception, action, cognition and emotion) and a platform of public Health. These teams have initiated and wil develop commun projects with the clinical units of the CHRU and COL. A strong collaboration between clinician and SHS researchers will be maintained in the framework of scientific programs developed in the SIRIC and in the aspects of knowledge diffusion.

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European Centre for Human and Social Sciences (MESHS) Management

Pr Fabienne Blaise - Director Contact    

Fabienne Blaise, +33 (0)3 20 12 58 30 2, rue des Canonniers, 59000 Lille Mail : [email protected]

Key figures / Key features The European Centre for Human and Social Sciences (MESHS) was created in January 2008, from the merger of the IFRESI (Federative Institute of Research on Industrial Economies and Societies) and the Erasmus International Institute. The MESHS is a research and services entity (USR 3185), under the control of the CNRS (National Scientific Research Centre) and various higher education establishments of the Nord-Pas de Calais and Picardie regions, including the 3 universities of Lille. It is part of the national network of Social Sciences Centres (http://www.msh-reseau.fr/). The MESHS is a “flagship project” in the framework of the 2007-2013 National/Regional Projects Contract (CPER) The MESHS works in cooperation with 30 partner laboratories: 9 university-CNRS research units, 20 university research teams, welcoming outside participants, and the laboratory of the Lille National School of Architecture and Landscaping. As a result of the participation of these laboratories, the MESHS can solidify the strengths of the Region in most areas of human and social sciences research (HSS), like, among others, anthropology, sociology, economy, geography, education sciences, Information and Communication sciences, law, or psychology.

Team involved in ONCOLille  CRD&P; EA 4487, Centre de recherches Droits et Perspectives du droit (Law and Legal Perspectives Research Centre) - The four teams within the CRD&P lab were graded A+ or A  EQUIPPE; EA 4018: Economie Quantitative Intégration Politiques Publiques Econométrie (Economy Quantitative Integration Public Policy Econometrics). Grade A  URECA EA 1059: Unité de Recherche en sciences Cognitives et Affectives (Unit Research on Affectives and Cognitives Sciences). Grade A  GERiiCCO EA 4073: Groupe d’Etudes et de Recherche Interdisciplinaire en Information et en Communication (Interdisciplinary Research and Study Group in Information and Communication).

Description (skills & resources) The MESHS support doctoral studies in their cross-disciplinary dimension, supporting (financially and logistically) cross-disciplinaary doctoral seminars of the three HSS graduate schools (“Human and Society Science”, "Legal, Political and Management Sciences", "Economic, social, land use and management Sciences") and the meetings organised to help with professional insertion of doctoral candidates. The mission of the MESHS is to support, organise and provide added value to HSS research by removing barriers and being a relay between laboratories and disciplines, as well as between human and social sciences and socalled "real" sciences. The Centre creates links between HSS laboratories, competitiveness clusters, regional concentrations of scientific excellence, businesses and local governments. Its scientific project is built around 3 orientations:

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 1) Health: between individual experiences and social dynamics;  2) Dynamics and governance of societies;  3) Texts, objects, interpretation, and argumentation. MESHS creates, supports, hosts and manages cross-discipline projects concerned by national and international tenders (ANR, European Union, etc). Since 2008, MESHS has obtained 58 contracts, for an approximative total amount of € 5,750,000. It hosts several health-related research projects. Five contracts have been granted in oncology since 2008, funded by the National Cancer Institute (INCa), National Cancer League, the APAS or the Foundation of France, SanofiAventis, Roche, Pink Ribbon International on the impact of breast cancer on subjective quality of life of young women and their partner, the overscreening and risk perception in BRCA1/2 hereditary cancer, the physician’s emotion regulation strategies and announcement of bad news in cancer and on personalised early active psychosocial accompaniment aimed at facilitating the return to work of women with breast cancer, psychometric validation of a breast cancer quality of life of young women and their partner. The MESHS also emits its own calls for projects for cross-disciplinary proposals: "CPER" (National/Regional Projects Contract) for cross-disciplinary framework projects (€30,000 for projects requiring an operating budget, €100,000 for projects requiring equipment purchases; 2to 3-year contracts); "seed" projects to help researchers prepare national and international cross-disciplinary framework projects (€5,000 for one year); "partnership" projects for projects organised by several laboratories (seminars, workshops), co-financed by the MESHS for €2,000 (for one year).

Main assets for ONCOLille Because it is upstream of research projects and wide-ranging, MESHS will favour collaborations between health and Social Sciences and Humanities (or SSH). Cancer research will benefit from its experience in terms of setting up and managing multi-sectoral interdisciplinary projects. MESHS will also foster, through its own calls for projects, seed projects which will be a first step in the preparation for national and international competitive calls. Eventually, one of MESHS’ objectives is to create a health-SSH platform which MESHS ideally aims at turning it into an interface linking the sphere of health, patients, their associations and the academia. This platform will aim at bridging the gap between scholars’ transversal issues to further refine the research issues and their determinants, and better match future research with everyone’s expectations and needs. It will not be about “monitoring" health research though; it will rather try and make sure it takes into account cross-disciplinary issues. Scholars in those fields (humanities and social sciences) will use the whole spectrum of concepts, references, and issues that are particular to their own disciplines to fruitfully confront individual reflections. MESHS invites foreign researchers and launches initiatives in scientific mediation and knowledge diffusion (monthly conferences, “SSH in the spring” – a thematic annual series of conferences in the field of humanities and social sciences, and various thematic scientific events). It also promotes SSH with events intended for local authorities and the corporate/business sectors in order for all social stakeholders to acquire a better grasp of the essential role SSH play in their decision-making processes and actions. SIRIC will clearly directly benefit from these proactive initiatives.

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“Lille Nord de France University - Research and Higher Education Cluster” (named PRES-ULNF for Pôle de recherche et d’Enseignement-Université Lille Nord de France) Management

Pr Christian Sergheraert – President Contact  Anne de Lamotte Tél.: +33 (0)3 20 29 93 82  1bis rue Georges Lefèvre -F- 59044 Lille cedex  http://www.univ-lille-nord-de-france.fr/

Key figures / Key features    

17 higher education institutions (Universities and high schools) 130, 000 students, 4, 600 researchers and research fellows 3, 000 doctoral students in 6 doctoral schools 200 laboratories of public research with about 2/3 tiers ranked A+ and A by AERES and associated to national research organizations. PRES-UNLF focuses largely on public research in the Nord-Pas de Calais region. It also supports the academic community to work in close collaboration with national research organisations and business and technologic clusters. All of its activities lead to development of the regional research and higher education.

Team involved in ONCOLille H Hondermarck, X LeBourhis, JF Bodart, T Lefebvre, N Prevarskaya, I Fournier, M Salzet, Y DeLaunoit, J Vicogne, V Fafeur, E Adriaenssens, F Soncin, D Tulasne, O Melnyk, N Delhem, M Duterque, R Bourette, B Quesnel, P Formstecher, A Lansiaux, R Polakowska, I Vanseuningen, M Cheok, N Porchet, C Preudhomme, JF Gossens, R Millet, P Chavatte, JP Peyrat, MC Copin, JL Lefebvre, D Chevalier, M Hebbar, E Lartigau, JP Triboulet, C Mariette, N Penel, S Fantoni, P Frimat, D Huglo, S Mordon, L Mortier, L Lemaitre, P Puech, A Villiers, N Reynaert, T Alam, F Briatte, A Maucourant, A Duhamel, J Foncel, JL Nandrino, V Christophe, P Antoine, A Mignon, S Chaudiron, G Blanchart.

Description (skills & resources) PRES-ULNF was founded in January 2009 in order to increase the regional academic potential, promote its visibility and enhance its international standing. It implements a plan of resource pooling of which:  a common project engineering to answer to national or european calls for proposal  a policy of purchase and maintenance of high shared equipments  a common scientific documentation  a cooperation and project strategy allowing a synergy around thematics able to federate institutions. It is in charge of coordinate the whole of regional answers to calls for proposal linked to the Plan “Investissements d’Avenir”. The PRES-ULNF has decided to gather the existing development structures in a “SATT” (Acceleration of Technology Transfer Company), a private company named “Nord de France Valo”. This new structure is being set up in association with the University of Picardie Jules Vernes (UPJV, Amiens), the University Reims Champagne Ardennes (URCA, Reims) and the CNRS. It is a valorization platformarticulated around several domains:biology and heath, agricultural sciences, chemistry and materials, information technologies and engineering sciences, and human and social sciences.

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Main assets for ONCOLille Valorisation, transfer and Partnerships For the health domain a specific department will be part of the SATT This department will gather complementary skills (scientific, business, legal and IP).The SATT activities will address in particular raising awareness, detection, maturation, protection and management of the intellectual property, business engineering,contracts, incubation, technology transfer, and project management. The SATT, as a unique service centre for researchers and companies, will become a privileged interlocutor for the competitiveness clusters in terms of identification of innovative projects and collaborative partnerships. Considering the research areas of the future SATT, the PRES-ULNF gathered with companies and research laboratories of our inter-regional area to develop synergy and cooperation through eight competitiveness clusters andin the health domain, aprivileged partnership with the competitiveness cluster NSL(Nutrition, Health, Longevity) will be established. The SATTwill constitute an important structure to support technologytransfer and valorization of the SIRIC scientific programs results.

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ONCOVET Management

Dr Dominique TIERNY Contact

Dr D. TIERNY Tel: +33 (0)3 20 34 41 34  Immeuble ONCOVET, Avenue Paul Langevin, 59650 Villeneuve d’Ascq

http://www.oncovet.net Key figures / Key features Oncovet is a private veterinary referral centre located on campus of “cité scientifique” Villeneuve d’Ascq (North, France) and dedicated to diagnostic, imaging and treatment of spontaneous cancer in dogs and cats. Oncovet has 11 years’ experience in these specialized activities and works with a regional international network of over 1000 veterinary practitioners in France and in the Benelux countries. Oncovet occupies a total surface of 1200 square meters with about 25 people. The team consists in 10 clinicians and several nurses offering surgical and cancer treatment facilities. Practitioners are dedicated to their own field of activity: internal medicine, medical oncology, diagnostic imaging (ultrasound, CT-Scanning, scintigraphy), surgery, chemotherapy and radiation therapy.

Team involved in ONCOLille D. Tierny, A. Hidalgo, F. Serres, L. Marescaux, C. Robat, N. Granger, H.Brissot, Elsa Edery, M.Pottier, E.Cathelain

Description (skills & resources) Most of the Oncovet clinicians had academic, clinical or teaching experience before entering the group and have a further university diploma in their specialist field. Most have collaborated with institutional medical research groups before (CNRS, Inserm). The clinicians have published over 25 referenced papers altogether in their fields and numerous articles in the French veterinary professional literature. Several veterinary theses have been written on the various internal oncology surveys. Oncovet has been working with different pharmaceutical companies and academic laboratories for clinical or preclinical research in the field of oncology for several years. Based on the caseload in small animal, the technical platform and the specialization of the senior scientists, Oncovet will provide individual training programs of residency to specialize in veterinary diagnostic imaging, surgery, oncology and neurology. The technical platform available at Oncovet is among the most highly developed in veterinary medicine in France : Radiography  SMAM Easymobil M32  KONICA Regius 110 (digitization and workstation)  GE Stenoscop (fluoroscopy)

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Ultrasonography:  ESAOTE MyLab 60 (transducers : convex 1-8 MHz contrast compatible, microconvex 3.5 -9 MHz, linear 6-18 MHz, phased array 1-3.5 MHz, phased-array 3.5-5 MHz) Computed tomography:  SIEMENS Somatom Spirit Nuclear medicine:  SIEMENS ECam Radiation therapy:  PANTAK DXT300 (orthovoltage radiotherapy)  NUCLETRON Microselectron (brachytherapy HDR)  ONCENTRA (workstation for dosimetry) Two surgery rooms, equipied for interventional catheterism Four animal housing Clinical laboratory: complete blood work, biochemistry, coagulation profile Hemodialysis Unit (HEMOTECH)

Main assets for ONCOLille A specialist referral oncology veterinary centre  A continuous flow of patient with spontaneous tumours, evaluated treated and followed up according to standardized protocols (2000 newly diagnosed patient each year). Our expertise field  Oncology, diagnostic imaging, internal medicine, cardiology, neurology, surgery, hospitalization, clinical pathology, and histopathology Our technical installation  Scanner, echography, scintigraphy, numeric radiography, fluoroscopy, endoscopy, orthovoltage radiotherapy, HDR brachytherapy, surgical installation, chemotherapy, hospitalization, laboratory of clinical pathology, histopathology and immuno-histochemistry on site Our team  10 specialists veterinarians  12 veterinary nurses, 2 medical secretaries, 1 clinical research responsible, 1 quality responsible

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I.3. Strategic considerations for ONCOLille I.3.1. A RESPONSIBILITY, A VISION AND AN AMBITION Being the region with the highest cancer incidence in France, our responsibility is to be able to make a definitive breakthrough in the understanding of two of the most significant biological and clinical issues in modern oncology: tumour and host resistance to loco-regional treatments and the role of tumour dormancy/persistence in clinical relapse. We have seen that currently the number of new cancer cases In France was every year > to 300,000 with an increase in an 89% increase in incidence since 1980. Demographic changes (increase of the general population and aging) have been responsible for almost half of that increase and the remainder has been largely explained by increases of breast and prostate cancer incidence through screening and early diagnosis (http://www.invs.sante.fr/surveillance/cancers/estimations cancers/default.htm). Between 1980 and 2005, the increase of cancer-related deaths (12%) was due to demographic changes, but the mortality risk rate decreased during the same period of time (-2.5% [men] and 1.2% [women] last 5 years). This divergence in cancer incidence and mortality trends in France over the last two-decade period can be explained by the combined effects of a decrease in the incidence in some aggressive cancers (stomach, lung in men) as well as changes in medical practices leading to earlier diagnoses and better care. When referring to data obtained by various departmental French cancer registries the Nord – Pas de Calais region displays the highest rate of cancer incidence and cancer mortality in France and one of the highest in Europe (http://globocan.iarc.fr/). For example, the over-incidence of hepatocarcinoma (HCC) is 40% (male) and 70% (female) higher in the Nord – Pas de Calais region than in France. When comparing the standardized rates in France and our region (http://www.orsnpdc.org/donnees/territoire.html), the mortality linked to oral cancers (mouth – lips – pharynx) in Men is 84% higher than in the other regions of France; this rate being one of the highest in the World. For oesophageal cancer, the mortality rate is roughly 75% higher in this region than in the rest of France (Men 83.8% and Women 58.4% in 2004-2007). Over the past years, social inequalities have been pointed out as an important parameter explaining the over-incidence of cancers in certain regions of France. This phenomenon has been exemplified by deaths linked to head and neck and oesophageal cancers in Men, which are respectively 4.4 and 5.2 times higher in the less-educated population than in the welleducated one (Menvielle G, Leclerc A, Chastang JF, Luce D. Inégalités sociales de mortalité par cancer en France : état des lieux et évolution temporelle. Bull Epidemiol Hebd. 2008;33:289-92.). Cancer deaths linked to social differences are mainly due to social inequalities of cancer incidence as well as cancer care. In the Nord–Pas de Calais region, this phenomenon is amplified but the risk factors associated to these cancers (smoking, alcohol, oral hygiene, HPV infection, educational and socio-economical levels…) do not fully explain all this over-incidence and over-mortality of preventable cancers. It is of great interest to better understand the co existing risk factors and their impact on over-incidence, over-mortality and survival in these cancers.

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Men Nb of cases in CLA

Women

Standard Incidenc e Rate in CLA*

Standard Incidence Rate in France*

CLA/ France Ratio

Nb of cases in CLA

Standard Incidence Rate in CLA*

Standard Incidence Rate in France*

CLA/ France Ratio

Head & Neck

198

46.5

21.8

2.1

37

6.9

5.2

1.3

Oesophagus

64

14.4

7.9

1.8

14

2.0

1.5

1.3

224

47.7

37.7

1.3

209

30.2

24.5

1.2

Liver

64

14.3

10.4

1.4

27

3.4

2.0

1.7

Larynx

44

9.5

7.1

1.3

5

0.7

1.0

0.7

320

70.9

50.5

1.4

75

13.2

12.6

1.0

6

1.1

1.2

1.0

4

0.4

0.4

1.0

35

6.9

7.6

0.9

32

5.3

8.8

0.6

645

139.2

121.2

1.1

Uterus

79

13.9

10.0

1.4

Ovary

68

12.3

8.1

1.5

Colon rectum

Lung Pleura Melanoma Prostate

Rate for 100 000 inhabitants per year standardized for the world population **Belot et al., Cancer incidence and mortality in France over the period 1980-2005, Revue d’Epidémiologie et de Santé Publique 56(2008) 159175 CLA = City of Lille area

ONCOLille can drive the leading oncology program in an area covering North West of France with the Cancéropôle Nord-Ouest (see chapter IV) and part of Champagne Ardennes (Reims), representing around 12 million inhabitants (1/5 of the global French population), area characterized by a very high cancer incidence (see following map). In addition to the epidemiological data which clearly indicate over-incidence and overmortality of these preventable cancers in the Nord–Pas de Calais region, the proposed research axes are directly supported by a strong expertise in clinical and basic research. Due to these considerations, the scientific, medical and political community of Lille and its region strongly believe that the reinforcement of existing collaborations could be very successful to bring new models and new explicative pathways in the field of oncology.

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Nord Pas- de- Calais

Cancer Mortality in France, 2004 - 2007

In 2010, Lille competed to the SIRIC tender but was not granted. The comments and recommendations of the reviewers at the time have been integrated for the 2011 answer. Based on our specific cancer incidence, the 2010 program was focusing on the concept of preventable cancers and recurrences. The limits in our 2010 organization have been totally considered in order to present a much stronger answer around fundamental and clinical research. However the social and clinical reality of our cancer incidence remains and the integration of human sciences is still strong in our 2011 project, together with fundamental and applied research projects. For these reasons, the medical and scientific community is particularly ready in 2011 to answer to the INCa tender, our program being totally, and even more, integrated in the framework of Plan Cancer 2 (2009-2013). ONCOLille has the legitimacy to develop an original project aims to achieve state of the art integrated research in some of the most important issues for oncology: tumour resistance and persistence after loco-regional treatments. Based on a large number of clinical and fundamental research programs in aggressive diseases (oesophagus, liver, melanoma, head &

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neck...) or most common diseases (prostate, gynaecology, haematology…), and on the existing level of excellence, the 2 integrated programs are: 

Program 1: tumour and host resistance to loco regional treatments in the field of head and neck, oesophagus, liver and gynaecological tumours.



Program 2: tumour dormancy and persistence in the field of haematology, melanoma and prostate cancer.

With the support of the partners from Political institutions (Regional Council) and the University of Lille-Nord de France, our vision is through ONCOLille to develop 2 global research programs supported by 4 integrated platforms.

With this project, we will reinforce the existing synergy between the research in human, social and life sciences. Moreover, the direct interface with the clinical research units will be crucial in the present research project. For example, the vast majority of oesophageal cancers seen in the Nord-Pas de Calais region is directly addressed by physicians to the surgical department of the University Hospital of Lille (Pr Mariette and Pr Triboulet) or to the oncology department of the cancer centre (Pr Adenis and Dr Mirabel) that are responsible for (i) extension diagnosis, (ii) multidisciplinary therapeutic strategy and (iii) inclusion in clinical trials. This large active patients‟ file is a unique opportunity for studying such population. The physicians involved are recognized international leaders.

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Targeting the biological mechanisms at the basis of cancer resistance and dormancy

A comprehensive research strategy from basic science to the patients benefit

A global and innovative approach to cancer care

Developing innovative therapies targeting resistance and dormancy

With ONCOLille, the integration of all disciplines in globally integrated programs is a reality. The impact of the 2 programs will be very significant in the comprehension of biological mechanisms of tumour dormancy, persistence and resistance to treatments and will drive treatment recommendations directed to the benefit of the patients together with impact on access to care and formalized follow up and reinsertion actions. They have the originality to stand on very strong basic or clinical research and to be able to achieve significant breakthroughs in the modelling of resistance to initial treatment and recurrence after treatment for the benefit of patients and healthcare providers. Our ambition is to be at term a European leader in these fields, driving innovative research, implementing new clinical research with up to date evaluation and modern knowledge dissemination.

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I.3.2. THE RESEARCH FACILITIES All the research facilities are fully described in part II. The ONCOLille Consortium gathers outstanding strengths of researchers in basic, translational and clinical research (labelled A+ and A teams) with very successful developments (genomic, proteomic, tumour bank, animal models, imaging, methodology...). However, we must insist on the capacity of ONCOLille to develop all the requested resources in the field of our projects, from basic sciences to human sciences through imaging & animal facilities, international clinical research and reference methodological evaluation.

  





40

As stated above, our tumour bank has been considered at the 2009 evaluation to be the one with the highest scientific value in France (see platform 1). Our imaging facilities cover all scopes from molecular to therapeutic tools with very innovative research in the field of Mass Spectrometry Imaging (MSI) (see platform 2). Our animal facilities cover all needed models with the originality of Oncovet. This veterinary clinic is the only one in France specifically devoted to animal oncology. It brings specific spontaneous tumour models which will be very valuable in program 2. The methodology teams of the CHRU and the Col have been at the forefront of clinical research evaluation. All clinical research is evaluated and granted at the national level by using tools (SIGAPS www.sigaps.fr, SIGREC www.cengeps.fr/Logiciel-SIGREC) developed in Lille (see platform Methodology and clinical research). Furthermore, the human sciences are a particularity of Lille with the daily interaction between HS researchers and clinicians in the field of oncology (see program 1)


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This original approach of bringing together the research facilities around 4 platforms, under the supervision of a single pilot, will help a lot for the coordination and the success of our programs.

I.3.3. TOWARD AN INTEGRATED RESEARCH CENTRE When answering to the INCa tender, the notion of integration is a key factor for the evaluation. ONCOLille is the archetype of such integration, bringing together academic institutions with a past history of multidisciplinary collaboration, research facilities around shared platforms, large research programs very well focused on important medical questions with a strong interaction with human sciences. Part of our legitimacy is based on the capacity to bring all fields of oncology together around pathologies which are very frequent in our medical surrounding: haematology, oesophagus, head and neck, mesothelioma, liver, prostate. All programs will integrate biological research, translational research, innovative imaging, clinical research and humans sciences developments, particularly in the field of comprehensive handling of the disease for the patient and the family (global care). To be successful, such a program must have a strong coordination, interactions with external cooperations, industrial partnership and valorisation, and must serve the population and the colleagues by a teaching policy. All these aspects are covered in our project and are synthesised in the figure and developed in the various chapters. ONCOLille will have the opportunity to achieve the scientific goals but furthermore, by getting the SIRIC label, to develop its attractivity to bring young researchers in the field of Oncology.

Management and organisation – E. Lartigau

INTEGRATED RESEARCH PROJECT Program 1 National and international collaborations program

Resistance C. Mariette

Program 2 Human and Social Sciences V. Christophe

Dormancy B. Quesnel

Platforms P. Formstecher

Biology

Imaging

Animal models

Y. De Launoit

Clinical research and methodology

I. Fournier

D. Tierny

A. Duhamel

Knowledge and practices dissemination program – S Fantoni

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Industrial Partnerships & valorisation program SATT – Eurasanté A. Coilliot

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I.3.4. MANAGEMENT AND ORGANIZATION OF THE SIRIC SCIENTIFIC ISSUES The global management of ONCOLille is described in following sessions. The main issue for us is the capacity to reinforce our already existing collaboration in order to develop the attractivity of our scientific and medical community. Based on the excellence of the research platforms and of the clinical research/methodology actors, the principle of ONCOLille management will be to reinforce the interaction by bringing new researchers in the field of integrated research in Oncology. Due to the deep involvement of the political community (Regional Council, Urban Community...), research in Oncology is already considered as a priority and getting the INCa SIRIC label will help us strongly to gain in attractivity. The role of ONCOLille management will be to continuously support emerging projects, develop exchanges on the ongoing projects, develop new approaches or initiatives, enhance valorisation and finally to disseminate through education. Through our scientific steering committee and with the help of our international scientific committee, ONCOLille will promote its research results at the European and International level.

I.3.5. CONTRIBUTION TO THE OBJECTIVES OF THE PLAN CANCER II The strategy behind the plan cancer is based on three major cross-cutting themes. These are the primary focus of the plan and are found in every area, expressed as specific measures and actions:  take more effective account of health inequalities to ensure greater fairness and effectiveness in all the measures taken to fight cancer;  encourage analysis and taking account of individual and environmental factors to individualise patient care before, during and after their illness;  strengthen the role of the referring doctor at every stage in the patient‟s treatment, in particular to improve quality of life during and after their illness. This is reinforced by 6 “flagship” measures: Measure 1 Increase resources for multidisciplinary research, by accrediting five multidisciplinary cancer research integrated sites Measure 3 Define environmental and behavioural risks. Measure 6 Produce and communicate information on cancer and cancer research and treatment. Measure 14 Tackle inequalities in access and take-up of screening. Measure 18 Individualise patient care and expand the role of the referring doctor Measure 25 Develop individualised social support during and after cancer. This plan will take account of individual needs in terms of medical supervision and psychological and social support. All these issues are clearly addressed in ONCOLille programs.

I.3.6. INTERNATIONAL COLLABORATIONS Cooperations have been already developed with local and regional biotech companies‟ trough the Eurasanté Incubator. Furthermore the existing regional (Cancéropôle Nord Ouest) and international (Belgium, Netherlands ...) cooperations will be strongly reinforced.

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I.3.7. VALORISATION STRATEGY The overall objective of the valorisation strategy will be to ensure ONCOLILLE as a leading European Oncology centre over the next five years. To meet this priority, the following key strategic actions will therefore be: 1. To transform research investment in IP 2. To develop of an effective partnership strategy with industry - By reinforcing numerous existing partnerships, - By developing new and fruitful partnerships 3. To develop a communication strategy that will enhance the attractiveness of ONCOLille In order to reach these goals, the technology transfer organization will be implemented in partnership with the future SATT Nord de France Valo and Eurasanté. EuraSanté and the members of the future SATT Nord de France Valo have a proven track record in the field of technology transfer, particularly in health and biotechnologies (see chapter V for examples of technology transfer successes in both PME and start up). These bodies will have a clear assignment, aiming to boost the technology transfer, the economic added value and the attractiveness of ONCOLille.

I.3.8. DISSEMINATION STRATEGY Dissemination of knowledge will be directed towards patients in the field of adapted follow up and professional reinsertion, as well as towards general practitioners (referring doctor) and political authorities. Trough a close collaboration with the faculty of medicine & the faculty of pharmacy and biological sciences, the most valuable results will be integrated in teaching (masters).

I.3.9. CONCLUSION The two integrated programs developed by ONCOLille, on the backbone of 4 state of the art integrated platforms combined with Human Sciences resources, will have the capacity to put all research forces in very close interactions. The reactivity of our research groups has been already demonstrated through the national evaluation of our Tumour Library or the participation of the Lille research team within the Nord Ouest Cancéropôle. As the history of collaboration and integration is already strong (C2RC) in Lille and due to the very high incidence of cancer in our Region, the INCa/SIRIC label will be given to a scientific and medical organization able to challenge europan comparable comprehensive cancer centres.

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II.

Presentation of the medical, technological potential of the SIRIC

scientific

and

II.1. Medical activity II.1.1. CHRU LILLE The Centre Hospitalier Regional et Universitaire de Lille (CHRU) is the only University Hospital of the Nord-Pas de Calais region (4 million inhabitants) and is the regional reference platform for most medical, surgical and technical activities (imaging, biology, functional explorations, information system). Developing new technologies, promoting research and training professionals, the CHRU of Lille has 2 965 beds (1091 in medicine, 868 in surgery, 231 in Gynaecology-obstetrics, 228 in long-term care, 148 in Psychiatry … ) with the expertise of 13.500 employees (including 3000 physicians). It plays a major role in the permanence of care including the emergency units with 120,000 passages, each year. In 2010, the CHRU de Lille hospitalized 93 671 patients and realized 1,192 290 consults, 5 200 births took place, and it registered 950 publications in scientific journals, and 9000 medical students were supervised. Responding to his missions in care, innovation & research and teaching & training, the CHRU de Lille allows equal access of patients to high-tech care networks through platforms in imaging (6 MRI‟s including 1 dedicated to research, 12 CT scanners, 7 digital angiographies, 7 gamma cameras, 1 positron Emission tomography), surgery (80 operating rooms, 1 surgical robot, 114 resuscitation beds and 95 beds of continuous monitoring) and others : 3 equipment for extracorporeal circulation, 59 renal dialysis posts, 16 surgical lasers, 1 Stereotactic radio-surgery (Gamma-Knife ®). One biology pathology Centre has been open in 2009 including 23 laboratories with common molecular biology and cell culture, dealing with 10 000 samples per day. The CHRU de Lille‟s activity represents 11% of the regional activity. It is the reference care centre for all the inhabitants of the Nord Pas de Calais Region (in 2010, 39% of stays concerned people who came from the entire region, outside the urban area of Lille) and also provides the role of "proximity" to the inhabitants of its territory health. The Academic Hospital has a yearly budget of 950 millions €. The expertise of multidisciplinary teams of CHRU de Lille, which was recognized by the certification of reference centres and skills centres, is based on medico-technical platforms and accommodations continuously upgraded through a policy of sustained investment: the CHRU annually invests around 50 million Euros. This effort was brought to 67 million Euros in 2010 for the launch of the implementation of "Project South," restructuring project of the South campus university hospital.

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II.1.1.1. ORGANIZATION OF CANCER TREATMENT AT THE CHRU The coordination of the oncology activities is ensured by the "Federation of Oncology ", which constitutes an internal network support. For each tumour localization, a multidisciplinary Committee of oncologists, pathologists, physicians, surgeons, radiologists, radiation therapists is organized. Every Committee is primarily responsible for defining the diagnostic and therapeutic strategies. More than 150 senior practitioners participate in these committees, articulated around the following clinical situations:           

Skin, Digestive Oncology (two sub-committees according to locations: liver/other locations), Endocrinology, Gynaecology and breast, Haematology (four sub-committees: leukaemia, lymphoma, myeloma and transplants), Bone metastases, Neuro-oncology, Onco-Paediatrics, Thoracic Oncology, Urology, Head and Neck and Eyes.

The Federation provides support, and especially medical psychology care coordination and liaison psychiatry (5 onco psychologists), patient education (stoma therapy, smoking and physical activity in connection with the Lille University Club), re-education - rehabilitation, nutrition, support for the pain, sexual disorders and fertility (including Ovarian conservation), social support and palliative care. The “Centre de Coordination en Cancérologie”, also known as 3 C guarantees the quality of the response to the different procedures for certification or accreditation ensures security of chemotherapy with Pharmacy and organizes the 26 annual training policies. It also coordinates medical secretariats of Oncology, manages the statistical database of multidisciplinary meetings, ensures the annual audit of the activities of the Federation. Patients‟ information Areas, “AIR cancers”, are specific sites delivering all general information on the disease prevention and treatment. “AIR cancers” also offers cultural activities in liaison with the media library of Lille University Hospital and with external partners (Museums). The Federation promotes patient support and encourages the emergence of innovative activities and scientific projects in the field of malignancies, and in particular the collaborations with Northwest Cancéropôle fundamental research units and laboratories. The Federation of Oncology from CHRU participates in connection with the Faculty of medicine - including its continuous medical education Department and Centre Oscar Lambret - to theoretical and practical teaching as well as continuing education for physicians, medical students and staff.

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II.1.1.2. CANCER TREATMENT The CHRU de Lille is the first institution within the north west interregion for cancer patients with 9 976 in-patients hospitalized in 2010 (95% of adults and 5% of children). On that scale, cancer patients represent 10% of all in-patients of the CHRU, and they also represent 16.2% of hospital stays of the CHRU corresponding to 29 251 stays in year 2010. The number of patients treated for cancer at Lille University Hospital has increased by 16.7% since 2005 (see below). 70% to 75% of these patients are new oncology patients. 2005

Nombre de séjours Nombre total CHRU Lille Nombrededeséjours séjours Nombre de séjours avec un code de cancer Nombre de séjours total CHRU Lille évolution / N-1 Nombre de séjours avec un code de cancer évolution / N-1

Nombre de patients (Adultes + Enfants) Nombre total (Adultes CHRU Lille +(source DIM) Nombrededepatients patients Enfants) Nombre de patients avec un code de cancer Nombre de patients total CHRU Lille (source DIM) évolution / N-1 Nombre de patients avec un code de cancer * NBévolution : données/ N-1 patients 2005 et 2006 = ONCODIM

2006

2007

2008

2009

2010

nb

%

nb

%

nb

%

nb

%

nb

%

nb

%

nb

%

nb

%

nb

%

nb

%

nb

%

nb

%

2005 2006 2007 2008 2009 2010 157nb547 % 165nb878 % 164nb660 % 172nb256 % 178nb012 % 180nb884 % 25 507 16,2% 26 509 16,0% 26 449 16,1% 26 979 15,7% 28 332 15,9% 29 251 16,2% 157 547 165 878 164 660 172 256 178 012 180 884 -0,2% 2,0% 5,0% 3,2% 3,9% 25 507 16,2% 26 509 16,0% 26 449 16,1% 26 979 15,7% 28 332 15,9% 29 251 16,2% -0,2% 2,0% 5,0% 3,2% 3,9% 2005* 2006* 2007 2008 2009 2010 2005* 84nb300 % 8 542 10,1% 84 300 8 542 10,1%

2006* 88nb458 % 8 701 9,8% 88 458 1,9% 8 701 9,8% 1,9%

2007 91nb140 % 9 072 10,0% 91 140 4,3% 9 072 10,0% 4,3%

2008 92nb966 % 9 302 10,0% 92 966 2,5% 9 302 10,0% 2,5%

2009 93nb671 % 9 650 10,3% 93 671 3,7% 9 650 10,3% 3,7%

2010 93nb483 % 9 976 10,7% 93 483 3,4% 9 976 10,7% 3,4%

* NB : données patients 2005 et 2006 = ONCODIM

Patients are mostly treated for digestive cancer, haematology, respiratory system cancer and metastatic locations.

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II.1.2. CENTRE OSCAR LAMBRET The COL is the regional reference cancer centre. As an academic hospital, it is only dedicated to care, research and teaching in the field of Oncology. The COL employs 780 professionals, including 96 doctors and scientists for a global budget of approximately 80 million Euros in 2009. Patient care is organized around multidisciplinary services, including surgical, medical and radiation oncologists. This organization, unique in France, guarantees that all aspects of cancer treatment are taken into consideration at one time. This expertise is maintained at a level of excellence by an ambitious professional training plan developed each year in consultation with Department Chairmen and managers of all logistical and administrative sectors. Every day, more than 100 health professionals are entering the Centre for training (students, junior doctors, engineers, biologists, students from para-medical schools …). Since 2008, the Oscar Lambret Formation Institute (IFOL), certified by the 3 national colleges of the continuous medical education, offers a catalogue of training themes. In 2010, training effort supported by the COL exceeded 1.7 million € for 780 employees. Certified in 2005 and 2009 by Haute Autorité de Santé, the COL has been classified first of the 20 cancer centres for quality of care and patient satisfaction in a survey conducted in 2009 by the Fédération Nationale des Centres de lutte contre le Cancer (FNCLCC). The medical imaging and radiation oncology platforms have been totally modernized (2 CT scanners, a 3T MRI, a PET CT, 1 CyberKnife, 2 Tomotherapy, 3 Linacs). The COL provides access to innovative diagnostic and therapeutic techniques, particularly in the following areas: surgery, oncogenetics, radiotherapy, imaging, brachytherapy, pathology and molecular biology, supportive care and pharmacology. The COL has since 2003 a Paediatric Oncology unit that supports the entire solid tumours of the children from Nord-Pas de Calais in association with the CHRU, and a pilot unit in aging patients. Most of the activities are labelled by the INCa. The COL has produced in 2009: 37,000 conventional days of hospitalization, 49 000 annual consultations, 4500 surgical acts, 50,000 radiation sessions, 20,000 out-patient chemotherapy treatments. 5 864 patients have been treated in 2010 at the COL.

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The research activities are under the authority of the Director of research, Prof. Eric Lartigau and subject to a regular evaluation by an external Scientific Council chaired by Professor Jacques Robert (Bordeaux). The COL develops research activities at the interface of basic research and highly specialized care (genetic testing, cellular targeting) and in integrated clinical research. An internal 27 review committee (Committee of clinical studies -CEC), meeting every month, investigates and selects all projects submitted for clinical research. Laboratory research is held in the laboratory of Dr. Amélie Lansiaux, MCU - PH at the Faculty of Medicine Henri Warembourg in anticancer Pharmacology and in the laboratory of Prof. Jean Philippe Peyrat in human Molecular Oncology. The Clinical research integrated unit (UIRC, see appendices) has an intense promotional activity that put the COL, in 2009, in the second position of the 20 CLCC (data FNCLCC 2010) with over 50% of the total PHRC selected in the Cancéropôle Nord-Ouest in the past 3 years. With more than 10% of his patients included each year in an interventional study, the COL is part of the rare health institutions to have exceeded the goal in clinical cancer defined in plan cancer At the regional level, the 3 cancer Centre of Lille, Caen and Rouen cooperate between within the framework of the "C cube" as an interregional platform in clinical research labelled by the League, which hosting the data Centre for Clinical Research (CTD INCa). Past 5 years achievements at the COL:  



 

48

2006: Coordination of supportive care. This action is following the definition of supportive care made in 2004 by the health authorities and as also present in the 2003-2007 plan cancer 1. 2007: Opening of the clinical research integrated unit equipped with 4 rooms to accommodate patients included in early phase (I, early II) clinical studies. Deployment of PACS (Picture Archiving and communication system). 14 June 2007: first patient treated with CyberKnife ®. 2008: 20 June 2008: inauguration of the Da Vinci Surgical robot. Development of the brachytherapy unit. First French centre in the number of treated patients, Centre Oscar Lambret has improved in July 2008 its equipment brachytherapy for the comfort of the patients. Dedicated radiotherapy simulation CT (90 cm) 2009: Creation of the Training Institute Oscar Lambret (IFOL) TomoTherapy machines January and May 2009). 2010: opening of the 3T MRI.


APPLICATION FILE

II.2. Research activity II.2.1. FUNDAMENTAL SCIENCES II.2.1.1. BIOLOGY ONCOLille combines biology research groups from CNRS & INSERM) as well as Universities (Lille 1, and 2, PRES). Most of the research activities are labelled at the national or international level (AERES, AICR, ligue contre le cancer, ARC, INCa, région NPC…). Research activities on cancer are already strongly structured. In fact, scientific, academic and hospital institutions are joined in a Committee of biomedical research and public health to define four priority areas: Cardiovascular and metabolic - Inflammation and Immunology - Neurosciences - Cancer. This research is carried out on three different geographic sites: the CHRU site, where research teams are in close interaction with the hospital, the “Institut de Biologie de Lille” (IBL), located on the “Institut Pasteur de Lille” campus and the University of Lille 1 campus. CHRU site The JPARC (Jean-Pierre Aubert Research Centre, UMR 837 Inserm-University of Lille 2-CHRU, Dir Pierre Formstecher) is localized on the CHRU site. The three research teams working on cancer (120 people in total) use molecular and cellular approaches, with a growing use of preclinical models. Teams are highly multi-disciplinar, putting together molecular biologists, cell biologists, clinicians, pathologists and pharmacologists. Research is focused on the identification of new molecular and cellular markers and targets for diagnostic and therapeutic approaches. Elucidation of mechanisms of resistance to therapy or of escape to immune survey is a common theme. The team “Factors of persistence of leukemic cells” (Bruno Quesnel) which focuses on the discovery of factors that contribute to the long-term persistence of leukemic cells such as minimal residual disease, relapse, and progression will lead the second scientific program of ONCOLille. The team “Molecular and cellular targeting for cancer treatment” (Pierre Formstecher) which focuses on the characterization of cancer stem or initiating cells in skin tumours and on the determination of the factors controlling their activation is also involved in WP2. The team “Mucins, differentiation and epithelial carcinogenesis” (Isabelle Van Seuningen) which focuses on the role of the membrane-bound mucins in epithelial carcinogenesis, particularly in oesophageal, pancreatic and colon cancers is involved in WP1. INSERM U703 unit (Serge Mordon), located on the CHRU site, is working on "Interventional therapies image and simulation-assisted" and is oriented towards minimally invasive therapies including laser therapy, surgery, radiotherapy, guided by multimodality imaging in preoperative simulation, per-operative planning (interventional imaging) or post-operative situations (followup, therapeutic evaluation). The scientific project is currently based on two axes: 1) new treatments of pelvic cancers and pelvic mobility and 2) support to vascular treatments. The PHARMACOLOGY UNIT of the COL (Amélie Lansiaux) develops both fundamental and clinical research projects. Studies are carried out on the adaptation of chemotherapy in patients with oral and oesophageal cancers in the aim to reduce toxicity and to bring maximal therapeutic effect. The laboratory of human molecular oncology (LOMH) (Jean-Philippe Peyrat) of the COL is devoted to the research of modifications of the BRCA genes in family with hereditary risk in breast and ovarian cancers. Calmette site (Institut Pasteur de Lille and IBL) UMR CNRS 8161 (Yvan de Launoit) focuses his interest on the identification of molecular mechanisms (from membrane receptors to transcription factors) by which a normal cell becomes tumoral, and finally metastatic. Research is performed by six independent and

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interactive teams. A special attention is given to reinforce the interdisciplinary programs. This is for example the case of the strong collaboration between the biologists studying the HGF/SF receptor, MET, and the chemists specialized in sugar potential inhibitor (deregulated MET signalling is involved in tumour progression) (Oleg Melnyk). More particularly, they study the initial events regulating the MET receptor; i.e. the proteolytic processing during development and tumorigenesis (David Tulasne). The first steps of tumorigenesis are decorticated through the molecular mechanisms by which a normal cell becomes pre-tumoral by escaping senescence and/or programmed cell death (Corinne Abbadie) or by which a tumour suppressor gene can be by-passed (Dominique Leprince). The tumour microenvironment crucial for the metastatic process is analyzed mainly via the role of the VE-statin in tumour neo-angiogenesis (Fabrice Soncin). Finally, interactions with the clinics are reinforced, particularly through programs on the immune response in HCV-related hepatocarcinoma, as well as TMPRSS2-Ets induced prostate cancer metastasis. The University of Lille 1 campus INSERM U908 “Growth factors signalling in breast cancer” (Xuefen LeBourhis) research activity is focused on the role of the neurotrophin family of growth factors in breast cancer, and their potential value for diagnosis and therapeutic intervention in this pathology. A particular attention is dedicated to signalling networks initiated by neurotrophin receptors and leading to cancer cell survival, proliferation, migration and metastasis. MALDI IMAGING TEAM (Isabelle Fournier) research is focused on the development of novel mass spectrometric methodologies and techniques for the investigation of the spatial localization of compounds in tissue leading to the reconstruction of two-dimensional molecular maps. INSERM U1003 “Ion channels in cancer” (Natacha Prevarskaya) is interested in the alterations of ion channel electrophysiological properties and molecular biology during prostate tumorigenesis. Indeed, ion channels determining the calcium signature would appear to be the best potential candidates as tumour markers and pharmacological targets so they are concentrating their research on the mechanisms of the regulation/modulation of several most promising channels. UMR CNRS 8576 “Structural and Functional Glycobiology” –UGSF (Jean-Claude Michalski) is one of the worldwide leader institute in the field of glycobiology. They developed numerous research activities in the field of cancer that bring important stones for the understanding of the involvement of glycosylation in the physio-pathology of cancers, and mostly of epithelial cancers (Philippe Delannoy and Tony Lefebvre). EA479, “Régulation des Signaux de Division” (Jean-François Bodard), is focused on the determination of the recruitment mechanisms and dynamics of molecular effectors activated either by the oncoprotein Mos or by Tyrosine Kinase Receptors.

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II.2.1.2. RESEARCH IN HUMAN AND SOCIAL SCIENCES AND PUBLIC HEALTH Research in human and social sciences applied to cancer is labelled at the national and international level and based both on existing teams having a long experience in health project and also on emerging resources with high potential for research against cancer. Research activities on cancer are already strongly structured on the MESHS, a federative “service and research unit” (USR 3185) under the tutelage of the CNRS and the Lille 3 University. It aims to structure and promote the research in social and human sciences in the region, acting as a go between laboratories but also between social sciences and exact sciences. They develop a program on Health with a part on practices, representations and norms, a part on Health politics and a part on relations between actors with the impact on medical care practice. Within the ONCOLille, we intend to strongly increase interactions between cognitive and informational sciences with public health, economics and quantitative methods like econometrics and applied statistics. Indeed, several projects focused on quantitative tools to assess from individual data the underlying process relating cancer morbidity and mortality to decisions linked to health behaviour and socio-economic conditions. Lille 3 University The URECA (Research Unit on Cognitive and Affective Sciences, EA 1059, ONCOLille contact. Pr Véronique Christophe). The scientific program of URECA concerns the modelling of the cognitive and the emotional processes that determine normal and pathological interactive behaviours for natural and artificial systems. A specific interest is devoted to the better understanding of the conditions and the dynamics of the emergence of human behaviour in the field of health psychology related to behavior, emotion, cognitive and familial aspects. More particularly, URECA is very active in translational programs and since 2005 they have interacted with CHRU and COL to develop pluridisciplinary projects in the field of the cancer supported by national and regional grants (INCa, National League of Cancer, Nord-Pas de Calais region etc). The EQUIPPE unit is specialized in econometrics, public policies, integration and quantitative economy (ONCOLille contact. Pr Jérôme Foncel). More particularly, they study times series, spatial statistics, forecasting, micro-econometrics which are topics that can be fruitfully applied to the definition and the evaluation of primary to tertiary preventive actions. The GERiiCO laboratory works on information and communication sciences (ONCOLille contact: Dr A. Lamy). They are interested in production, transmission, diffusion and appropriation of information, knowledge, text, and representations in contemporary and modern society. They have methodological and analytic skills in information and communication sciences, social sciences that are instrumental to analyse how people understand health information. They are implicated in 23 ministerial programs and 3 regional programs of which one in health domain. The integration of research in the field of oncology is planned for the purpose of knowledge dissemination. Lille 2 University The CRDP « centre de Recherche en Droit et Perspectives du Droit, EA 4487 » (ONCOLille contact Pr P Frimat & Dr S Fantoni). Multidisciplinary projects are elaborated in between law and medicine /pharmacy research teams. The study and research centre in « Health-employmentenvironment » develop within the EA 2694 a theme on public health with a section on epidemiology of chronic diseases and a section on modelling with biostatistics and information sciences.

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II.2.2. CLINICAL RESEARCH II.2.2.1. CHRU LILLE The CHRU de Lille is the 4th university hospital in France in terms of scientific publications, the 3rd in clinical research: Each year, the CHRU de Lille sponsors nearly 70 new studies and is investigator centre in nearly 900 studies (academic or industrial). In 2010, more than 4000 patients have been included in clinical trials among:  

500 trials promoted by institutional and academic structures representing 2 262 inclusions 383 industrial trials representing 2 000 inclusions

Particularly in the field of oncology, the CHRU de Lille promoted 24 studies in 2010, representing 428 inclusions, and was investigator centre for 298 studies in 2010 representing 685 inclusions:  

159 institutional and academic trials representing 293 inclusions 139 industrial trials representing 392 inclusions

Thus, oncology field represent in the overall clinical research activity of the CHRU de Lille:  

13% of overall number of studies promoted by the CHRU, representing 21% in terms of inclusions. 34 % of overall number of studies for which the CHRU is the investigator centre, representing 16% in terms of inclusion.

Clinical research activity grows continuously since 2006, as presented below: Tableau 1 : Number of cancer studies by sponsor

Year

CHRU

Academic

Industrial

Total

2006

15

112

84

211

2007

13

111

68

192

2008

16

139

100

255

2009

20

169

126

315

2010

24

159

139

322

Tableau 2 : Number of cancer patients by sponsor

Year

52

CHRU

Academic

Industrial

Total

2006

116

202

142

460

2007

91

282

146

519

2008

287

325

154

766

2009

317

201

279

797

2010

428

293

392

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Organization of clinical research The CHRU de Lille has for over fifteen years initiated a dynamic support to clinical and basic research, through the creation of the "Delegation for Research and Innovation" (DRCI) covering both aspects. The CHRU de Lille was the first University Hospital in France to co-sign the four-year contract between the University and French Ministry of Higher Education and Research, and an agreement with the University of Lille 2 and INSERM. A tight link exists between CHRU, University, Inserm and CNRS with the constitution of mixed and multi competent teams. These collaborations allow the creation of a university biomedical research structure, the “Institut de Médecine Prédictive et de Recherche Thérapeutique » (IMPRT) and the organization of the « Clinical Research Federation ». Furthermore, the CHRU and the PRES “Lille Nord de France”, in close connection with Eurasanté and Inserm, have shared their activities of economic valorisation in creating BIOVALO, a structure for the valorisation of the biology-Health section. Under the responsibility of the Delegation for Research and Innovation, the Clinical Research Federation (FRC) is responsible for:  

the instruction and the assistance in drafting clinical research projects which CHRU de Lille is going to promote the operational implementation of institutional and industrial clinical research projects.

The Clinical Research Federation‟s primary role is to assist the development and set up of clinical research projects, from their submission to their operational implementation, using staff, skills, resources and labelled structure inside the CHRU like the « Centre d‟Investigation Clinique », the « Centre de Resources Biologiques », and others investigation support platforms. The Clinical Research Federation (FRC) has 3 main objectives: 





group together in a single structure the teams involved in professionalization of clinical research on campus: the promotion unit, the « Centre d‟Investigations Cliniques » (CIC), the « Centre de Resources Biologiques » (CRB), the « Centre d‟Innovations Technologiques » (CIT), the biostatistics unit… pooling of human and logistical resources assigned to clinical research, particularly medical and non medical who received special training in clinical research, in order to harmonize practices, recognize and develop employment of research professional‟s policy, offer investigators and biomedical sector professionals a single window providing: (i) the definition of clinical trials (methodology, logistics, medical and regulatory aspects and financial), (ii) the implementation, monitoring and quality assurance of clinical trial.

In practice, through the FRC, the Delegation for Research and Innovation of the CHRU de Lille :  



53

assist investigators in the establishment of their protocols (methodology, law, logistics, financials aspects…) through consulting and support units. coordinates and monitors the progress of projects in promotion, by its pool of Clinical Research referents, monitoring and controlling the quality of the protocols, which is inherent to the responsibilities of the insitutionnal promoters ; provides investigators, when needed, the staff (ARC / TRC and other staff) required for the day to day investigation activity linked with clinical studies.


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Clinical trials of the CHRU are conducted in: 

 

The blood diseases unit, based at Hôpital Huriez at the CHRU in association with the 7 units of haematology of the Fédération d‟Hématologie Régionale (CH Lens, Valenciennes, Arras, Dunkerque, Roubaix, Boulogne et l‟Hôpital St Vincent de Paul du GHICL), takes in charge the regional clinical research activity of adult leukaemia and lymphoma. The centre has a sterile sector where bone marrow allograft are realized for adult patients of the whole region of Nord-Pas-de Calais, and it has access to all technical platforms of the campus. The paediatric haematology unit of Hôpital Jeanne de Flandre CHRU-Lille, which also work in association with a regional network, The multi-thematic CIC (Clinical Investigation Centre-Inserm, recently evaluated A+), with a personnel dedicated to clinical research (physicians, engineers, clinical research associates and technicians, administrator, data managers, …). It has specific premises (7 adult beds including one with laminar flow, 4 paediatric beds), surveillance materials, data recording facilities, a laboratory for preparation and pre-analytic treatment of biological resources (PSM, …) under control atmosphere type L2, adaptable L3. Volunteers are taken in charge in the centre in different ways: external consultations, day hospitalization, short term hospitalization, and regular hospitalization.

Partnerships are particularly rich with imaging and nuclear medicine platforms, biology and pathology centre where is located the tumour bank, the biological resources centre and the central pharmacy and its clinical research sector (cytostatics reconstitution unit). Pathologies taken in charge in these units cover the whole adult and paediatric haematology and hematopoietic cellular grafts principally in onco-haematology The recognition of the Lille‟s site at the national and international levels is expressed by almost permanent external solicitations for participation in therapeutic trials, as well as the implication in 36 international groups and European infrastructural projects (ECRIN, BBMRI). Pharmacovigilance is involved in a European FP7 project "PSIP" (Patient Safety-through Intelligent Procedures in medication) and obtained funding from the EU up to 7.27 million euro. A specific analysis of patients enrolled in early phase will be down also by this tool. Moreover, particular attention will be paid to early phase trials in children to meet the needs expressed in the Paediatric Investigation Plan and the European regulation on medicines for children recently adopted by the European Commission.

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II.2.2.2. CENTRE OSCAR LAMBRET –THE CLINICAL RESEARCH UNIT The Integrated Clinical Research Unit (UIRC) of the Oscar Lambret Cancer Centre assures the development of clinical research of this establishment in accordance with the orientations and the objectives recommended by the external scientific council and in conformity with regulatory dispositions and Good Clinical Practice Guidelines. This unit is composed of administrative offices, 8 rooms with beds and medical chairs for patients within the same physical area specifically attributed to clinical research. The unit was conceived as an interdisciplinary platform dedicated to clinical and translational research and has allowed the inclusion of 706 patients in 158 interventional studies, which represents 12.8% of the active file of the establishment. Its 3 missions are the following: The UIRC of the Oscar Lambret Cancer Centre is a pluridisciplinary investigation site open to all players in the Region Created in the middle of the 90‟s, the Clinical Research Unit, which became the Integrated Clinical Research Unit in 2006, coordinates and centralises all the clinical research activity of the Centre Oscar Lambret Cancer Centre. As of June 2010, the staff of the UIRC investigation unit included 4 full-time ARC (including one ARC CENGePS) and 7 equivalent full-time TRC (Clinical Research Technicians). Each ARC and each TRC is in charge of one or two cancer sites. One ARC is responsible for applying quality control procedures. Since 2007, the UIRC disposes of a care unit specifically dedicated to taking care of adult cancer patients included in early phase clinical trials (phase 0, 1 or 2). This care unit is under the medical responsibility of Pr Antoine ADENIS and is in possession of an authorisation for research which was renewed in 2010, in conformity with the new regulations: “Biological research for scientific purposes and notably clinical trials of first administration in Man (drugs destined for human usage, medical apparatus), trials in radiotherapy and translational research”. The investigators intervening within the UIRC all received training in Good Clinical Practice. The implantation of UIRC facilitates the taking care of patients, since it benefits from a privileged geographical position in the establishment. It is situated within immediate proximity to the outpatient hospital, as well as the Internal Pharmacy Usage (PUI) and the external consultations. With its 8 beds and medical chairs, the UIRC is perfectly adapted to the ambulatory administration of galeneic formulations actually developed in oncology (oral route, infusions of short duration). The head nurse who is responsible for the supervision of health care personnel affected to the unit, has an ARC qualification. Besides the planning and the coordination of patient care, he elaborates, for the patients of each new study, the procedures for specific care, taking into account the requirements and constraints of each trial. At the present time, the nurse team is composed of 2 IDE (Infirmier Diplômé d‟Etat), whose jobs are occupied by experienced clinical research nurses of the Centre. In order to follow the constraints of the protocols, the patients included in the trials benefit from reserved time slots for imaging tests as well as functional imaging. The Early Study Projects are managed and conducted by a single organisation allowing a rapid implementation of the study (mean delay of 2 weeks after receipt of the CPP (Comités de Protection des Personnes) and AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé) authorisations, once the internal authorisations of the CEC (Commission des Etudes Cliniques) of the Centre have been obtained. This commission meets monthly and insures the scientific importance of each study in accordance with the strategic and political orientations of the Centre and its external scientific council. If necessary, extraordinary meetings of the CEC can be organised for rapid decisions depending on the importance of the proposed study.

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The UIRC of the Oscar Lambret Cancer Centre as a study sponsor is dynamic and efficient Since 2004, the UIRC reinforced its activity as a sponsor of clinical trials (essentially phase II trials). It provides methodological support, regulatory and logistic documentation for the development of projects planned by investigators of the Centre. As such, it centralises and also sponsors projects susceptible to enter into the scope of grant proposals from INCa (Institut National du Cancer), notably the PHRC. The sponsor unit comprises 1 ARC project leader and 1 ARC monitor, an assistant administrative manager of trials and a data entry operator. The development of these projects is carried out with the support of the Methodology and Biostatistics Unit of the Oscar Lambret Cancer Centre, under the direction of Andrew Kramar since april 1st 2010. Since 2007, all the data from studies analysed by the Biostatistics Unit were managed by the North-Ouest Cancéropole Data Treatment Centre (CTD-NO), according to the standards in use. Moreover, a partnership exists with EA2694 (Santé Publique, Epidémiologie et modélisation des maladies chroniques/ Pr A. DUHAMEL) which is attached to the Biology and Health Doctoral School and which has a recognised expertise in the fields of data-mining, medico-economic analyses, and bio-informatics. Finally, the pharmacovigilance of the studies sponsored by the COL is assured by UIRC (Dr Stéphanie CLISANT) who passed the Eudravigilance assessment. The sponsorship activity is sustained with 507 and 432 patients included in France in trials sponsored by the Centre Oscar Lambret Cancer Centre in 2009 and 2010 respectively. This activity allowed the UIRC to receive financial assistance for 19 PHRC since 2003, 9 of which were obtained within the last 3 years (3 in 2008 ; 2 in 2009 ; 4 in 2010). The partners implicated in the translational part of these clinical studies: The Cancer Pharmacology Laboratory (Dr A. LANSIAUX, MCU-PH), and the Human Molecular Cancer Laboratory (Pr JP. PEYRAT) of the Oscar Lambret Cancer Centre. The UIRC of the Oscar Lambret Cancer Centre is also a training and research site for Behavioural Sciences The UIRC is a training ground for medical internship (DES Medical Oncology and DESC of Oncology) as well as pharmacy and students from ILIS (Institut Lillois d‟Ingénierie de la Santé) who are in training for jobs as TRCs and ARCs. More recently, interdisciplinary research activities were developed in partnership with the Lille Nord de France University (Dr V. CHRISTOPHE) on the subject of the patient‟s perception and comprehension of informed consent, the study of the psychological and emotional impact of patient participation in a cancer clinical trial, or how doctors live with the announcement of bad news. Four transversal projects are in progress and are entirely supported by INCa, the Ligue Nationale contre le Cancer, the Fondation de France and pharmaceutical industries The Cooperative Sanitary Group “Centre de Référence Régionale en Cancérologie (C2RC)” created by the COL and the CHRU of Lille favourites cooperations in the domain of clinical research in oncology between the two establishments. The C2RC has as an objective the development of a common medical and scientific project between the CHRU of Lille and the Oscar Lambret Cancer Centre. Under the auspices of the CIC of the CHRU of Lille, the two establishments signed a contract in 2008 which enabled clinicians of the CHRU of Lille to openly cooperate with the UIRC of the COL.

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II.2.3. TRANSLATIONAL RESEARCH The CHRU blood diseases unit participates in fundamental research in the domain of the mechanisms of tumour dormancy in collaboration with the laboratory of the faculty of pharmacy and pre-clinical models are in development (Pr Quesnel, Inserm 837). The emergent translational clinical research activity is now structured and permits participation in a dozen of trials since 5 years. In 2009, 168 therapeutic trials were initiated in the blood diseases unit:  

87 trials with a public organism or cooperating group as sponsor (119 inclusions, 433 active patients) 78 trials with an industrial sponsor (150 inclusions, 255 active patients)

Activity in early phases (phases 0, preferentially called “exploratory”, phases I, and phases II) is regular since 2000, with the participation in 135 trials (1 phase 0, 14 phase I, 20 phase I/II, 100 phase II) from a dozen projects per year to reach 21 new protocols in 2009. 64 were still active phase studies with a queue of 185 active patients until the 31th of December 2009. This has contributed to the obtainment of the AMM of ZEVALIN®, GLIVEC®, REVLIMID®. In 2009, 19 trials concerned phases I or I/II with a first administration to man, 62 phases II. Many of these trials are pivot ones for registry of new molecules in oncology. Beside investigators and medical teams, clinical research team, directed by Dr. Marie-Odile Pétillon is composed of:    

57

1 senior clinical research technician, in charge of the coordination, training and managing of the clinical research technician team and working for 4/5 of time. 10 clinical research technicians 7.5 full time. 1 clinical study nurse in charge of patient‟s hospitalization. 2 secretaries for document‟s management and office work.


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II.3. Presentation of the SIRIC shared resources and facilities II.3.1. 4 INTEGRATED PLATFORMS To be more efficient, we have developed the concept of Integrated platforms defined as “shared resources including facilities, infrastructures and human competences dedicated to the scientific programs for research and training”. The CHRU of Lille and its partners have at their disposal a pool of integrated platforms and biological resources that provide them the necessary equipment to develop innovating research projects in the field of cancer. Equipped with state-of-the-art apparatus and staffed by highly specialized personnel, the Integrated Platforms will provide support services with highly competitive technologies and will actively participate in research projects, platform networks, technology development projects and agreements. They are characterized by their strategic value, which makes them core assets for the implementation of public and private research. They represent another originallity of the program with the capacity to mobilize all facilities in a combined way, in order to make possible the programs with the best possible efficacy.

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II.3.2. INTEGRATED PLATFORM 1: BIOLOGY To tackle the biological questions raised in the two scientific programs, the present project will benefit from all the top-quality expertises available in Lille and more particularly within the CHRUCOL, Lille 1 and Pasteur Institute campuses. In fact, they have at their disposal a pool of biological technology platforms and resources that provide them the necessary equipment to develop innovating research projects in the field of cancer, for example to decipher the molecular pathways directly involved in tumour resistance and tumour dormancy. Over the last years, the functional genomic platform permitted to identify new crucial genes involved in acute myeloid leukaemia. Now, it will be applied to tumour dormancy and immunoevasion projects for this disease, as well as for the solid tumours studied in the second scientific program. In fact, this facility will identify and analyze genetic alterations (DNA and RNA) such as mutations and/or overexpression of receptor tyrosine kinase (RTK) and mucin genes (first scientific program) or specific factors associated with tumour dormancy in AML, melanoma and prostate cancer (second scientific program). A top-quality tumour library platform common to the CHRU and the COL will play a key role for the success of this project, more particularly the identification of the tumour samples necessary for the goals here above mentioned. Proteomic studies (in coordination with the Glycobiology platform) will also be performed in both scientific programs, and more specifically new cell determinants and signalling pathways involved in resistance (signalling of RTK). This project will also reinforce the collaboration with the Peptide Chemistry platform to characterize new RTK inhibitors. The key results obtained in these programs will be translated into pre-clinical mouse models (spontaneous/induced or humanized models...) for example to determine physio-pathological processes linked to primary or secondary tumour resistance (oesophageal cancer) or tumour dormancy and immunoevasion. The more promising data obtained on mouse tumour models will be developed in dog and cat by Oncovet pharma which has a large access to animals with spontaneous tumours. The use of these spontaneous tumour models arising in dogs and cats with similar natural history and response to treatment will be a great value (originality) in the ONCOLille program. Equipped with state-of-the-art apparatus and staffed by highly specialized personnel, the Biology Platforms of the site provide support services with highly competitive technologies. These platforms not only offer services but they also actively participate in research projects, platform networks, technology development projects and agreements. These platforms are characterized by their strategic value, which makes them critical for the public and private research and development sectors. The main activities developed by the Integrated Platforms are devoted to research support, technology development (establishment of new methodologies) and research projects and they can be co-managed by several institutes demonstrating the aptitude to work in synergy for technical, medical and research staff. Indeed, these resources are accessible to the whole of the Lille scientific community with a specific organization and often with a scientific committee which evaluate the appropriateness of the project with the proposed technical resources. Some of them are federated at the regional level and detain the national label “IBiSA” (“Infrastructures Biology Santé Agronomie”) allocated by the AERES (“Agence d‟Evaluation de la Recherche et de l‟Enseignement Supérieur, i.e National evaluation agency for research and Higher education). This label is a guarantee of excellence and opening of the platforms. The platforms are also highly active in terms of education to the use of new tools and in technology watch. The regional scientific community uses every effort to open the integrated platforms to the researchers and to favour interactions between clinicians and fundamental researchers. For example, the organization of “clinicians-researchers day” within the context of the PHARE-project “cancer” of the CPER (Contrat Plan Etat Région) had a strong impact on the development of translational research in the region.

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Functional Genomic Platform Management and contact

 Dr Martin Figeac – manager of the Genomic platform, IRCL  +33 3 20 16 92 20  [email protected] Location 

CHRU, Place de Verdun 59045 Lille cedex

Key figures / Key features The objective of the genomic facility is to empower the biomedical teams working in the field of cancer in particular, to develop large scale genomic project and assist them in exploitation of the generated data.  Belonging to the multisite platform LIGAN (labelled IBiSA), this equipment was certified by IBiSA (BiologyHealth-Agronomy Infrastructures) in 2009. The network LIGAN provides access to the latest high throughput genotyping tools (454/ HiSeq-2000 / SOLiD, iSCAN, Bead Array and Bead Express).  90% of its activity is dedicated to cancer.  Localization of the platform inside the CHRU site, giving an easy access for SIRIC projects  A high-qualified permanent team : 11 people, 6 working on molecular biology aspects and 5 on bioinformatics, biostatistics and IT. The functional and structural genomics platform conducts about 30 projects a year involving about 1000 samples analyzed. The platform is deeply committed to cancer research projects and has been involved in many high level publications in the field.

Team involved in ONCOLille - Lille 2 University – IFR-114 – IRCL – UMR 8161, UMR Inserm U837 E3 and E4, Laboratory of haematology CHRU

Description (skills & resources) Since May 2009, 4 distinct and complementary technical units :  AGILENT and AFFYMETRIX, which involve the most widely used microarray technologies  SOLiD 4 system, devoted to high throughput sequencing (enables the resequencing of entire genomes or more pragmatically targeted DNA genome regions, and also to quantify transcripts mRNA and small RNA, to reconstruct different isoforms and their mutations, as well as to quantify epigenetic processes.  The Bioinformatics Unit, manages computerised and statistical studies of results obtained with DNA chips and by sequencing. The platform is part of the LIGAN-MP (personalized medicine LIGAN EQUIPEX) and will develop in the next ten th ut nd rd years high roughp sequencing (2 and 3 generation) for patient care.

Main assets for ONCOLille Genomic platform will supply technical support to the realization of SIRIC projects in the identification and analysis of genetic alterations, in basic research and in translational research. For example :  Identification of mutations and/or overexpression of RTK (MET, EGFR …) genes and MUC genes (program 1)  Characterization of specific factors associated with tumour dormancy in experimental melanoma (program 2)  Translational research for the program 1 (predicting relapse - acute myeloid leukaemia)

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Tumour Bank Management and contact  Marie-Christine Copin, Coordinator of the C2RC tumour

bank and of the regional network  +33 (0)3 20 44 49 85  [email protected]

Location  Centre de Biologie et pathologie – CHRU – 59000 Lille

Key figures / Key features The function of the tumour bank is the cryopreservation of cell and tissue samples suitable for molecular studies relating to DNA, RNA and proteins. Its mission is to organise and manage collections of frozen tumour cell and tissue samples and as frequently as possible healthy tissue samples from CHRU and COL, together with biological and clinical annotations. The samples come from the CHRU and COL, but also from other private or public establishments in the region, via the regional tumour bank network (approved and funded by INCa, 60 healthcare establishments or anatomical pathology laboratories). In this way, the tumour library contributes to the development of oncology research aimed at improving diagnostic and therapeutic care of patients (1,079 samples were used for research in 2009), as well as the development of diagnostic, prognostic and therapeutic innovations in oncology, excluding cell therapy.

Team involved in ONCOLille  CHRU: Pathology department and haematology laboratory  COL: Pathology department  UMR 8161, U1003

Description (skills & resources) Staff: Surgeons, pathologists and oncologists are implicated in the management of the resources. Equipment:  In 2009, the HCCRB software application was installed (Technidata) for the management of the samples in the Lille CRRC tumour bank and all the tumour banks within the Cancéropôle Nord-Ouest cancer hub.  Appropriate data are available for each type of cancer in the HHCRB software application. Recent developments:  Grant of €250,000 obtained from INCa for the organisation of the molecular pathology centres.  Application for “IBISA” accreditation: budget of € 45,000 obtained to support the tumour library’s quality assurance system (employment of a part-time quality technician). A high level of scientific production: in 2009, 11 publications for cell library, and 7 publications for tissue library.

Main assets for ONCOLille The tumour library plays a fundamental role in the development of preclinical and applied research in oncology, offering researchers the means to access comprehensive sets of biological samples linked to broad clinical and biological data. For ONCOLille, tumour library will support the scientific programs :  the first one, particularly in the study of the role of the membrane partners of RTKs in resistance to locoregional treatments (mucins and oral and oeso-gastric cancers)  the second one : in basic research (intracellular calcium and membrane ion channels in prostate cancer, bone metastasis in prostate cancer) and in translational research for predicting relapse in acute myeloid leukaemia

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Tumour genetic Management and contact

Pr. Nicole Porchet – Medical manager of the platform, CHRU  +33 (0)3 20 44 61 54  [email protected] Location

 CHRU Lille, Centre de Biologie et Pathologie, 59 000 LILLE Key figures / Key features The CRRC Tumour Molecular Biology Platform was set up to carry out newly-developed molecular tests as part of the care of cancer patients in the region. The tests relate to predictive markers which will determine patients’ access to particular targeted treatments, markers of diagnosis or prognosis or for follow-up of residual disease. The molecular tests complement the anatomical pathology diagnosis for all cancers, or the biological diagnosis for leukaemia. The CRRC’s biologists belong to national networks for the purpose of standardising tools and quality control and the CRRC pathologists belong to diagnostic expertise networks in fields for which molecular analysis is essential (sarcomas, lymphomas, brain tumours). 2010 workload: over 6000 tumours analysed (half in haematological oncology, half solid tumours); approximately 20,000 tests carried out.

Team involved in ONCOLille  CHRU Haematopoietic tumours : Cellular haematology department (Prof. C PREUDHOMME), Haematological oncology cytogenetics training unit (UF), Medical Genetics department (Dr JL LAÏ)  CHRU Non-haematopoietic tumours (solid tumours and sarcomas) : Anatomical pathology and cytopathology Institute (Prof. Marie-Christine COPIN), “Endocrinology, metabolism, nutrition and oncology” biochemistry and molecular biology department (Prof. Nicole PORCHET), Joint Molecular biology, genetics and cytogenetics platform of the Biology Pathology Genetics Centre of the CHRU Lille (Prof. Nicole PORCHET)  COL Non-haematopoietic tumours: breast cancer : Human Molecular Oncology Laboratory (Prof. JeanPhilippe PEYRAT); Anatomical Pathology and Cytopathology Laboratory (Dr Yves-Marie ROBIN)

Description (skills & resources) Multiple facilities including :  Tools for Molecular biology: 5 capillary sequencers, 1 pyrosequencer, 2 real time PCR systems, automated preand post-PCR systems pending delivery; 1 next generation genome sequencer (GS Junior Roche) in the process of being purchased; 1 Agilent array CGH platform, 2 automated DNA extraction systems.  Culture platform with an L2 laboratory for the study of human cells, yeasts and bacteria for molecular biology cloning. The workload is continuously growing: work on solid tumours (number of analysis) has increased by nearly 60% between 2009 and 2010 and in terms of haematological oncology work (regional and national), 15927 analyses were performed in 2010, according to a 61 biomarkers list.

Main assets for ONCOLille  The platform is currently involved in different activities in basic research, translational research and diagnosis fields and is in close interaction with researchers and clinicians of the site.  Expertise in related activities and quality of service  Location of the platform inside the CBP ; giving an easy access for the SIRIC’s teams  Particularly, the platform will provide useful tools for identification of the role of the membrane partners of RTKs in chemoresistance.

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Proteomic and glycobiology platform Management and contact

Pr Christian Rolando – Director, Laboratoire de Biophysique, Faculté des sciences pharmaceutique et biologiques +33 3 20 43 49 97 [email protected] Location  University of Lille 1, Cité scientifique, 59655 Villeneuve d’Ascq

Key figures / Key features Localized in the University of Lille1, the proteomic and glycobiology facility is a multi equipment tray from proteomic to glycotechnologies. The proteomic platform is labelled IBIsa.

Team involved in ONCOLille UMR 8161, INSERM U908, UMR CNRS 8576, U837 E3 and E4

Description (skills & resources) Common centre of mass spectrometry - Scientific coordinator: Christian ROLANDO :  Material: MALDI-TOF, ESI-ion trap et logiciels dédiés, Nano-LC couplée au piège ionique  Users: All units if the IFR, external academics (IMPRT, Institut Pasteur, IBL) for 30 %, and industrials for 10 % Tray of proteomic Hi_Prot Scientific coordinator: Caroline TOKARSKI  Material: Mass spectrometers, systems for Sample preparation, Robots, Bidimensional electrophoresis, Software of imaging analysis, Quantitative Proteomics, Data treatment  Users: IFR : 50 %, external academics 20 % (CHR G. Pompidou, Musées de France, O. Lambret Centre), Industrials : 30 % (Etablissement Français du Sang Nord-de-France, Biosynthec) Tray of glycotechnologies Scientific coordinator: Jean-Claude Michalski  Material: Chromatograf, phase gaz, HPLC, MALDI TOF/TOF et ESI Q-TOF (common with proteomics), Enzymatic analysis and lectinic, Chemistry Fragmentation, Spectromètre RMN Avance 400 MHz (9,4 Teslas) (Centre Commun de Mesures RMN de Lille 1)  Users: IFR : external academics (IMPRT, Pasteur Institute of Paris and Lille, IBL, French and foreign universities, CNRS, INSERM), Industrials (Sanofi, ASSAPS, Fabre). Plasmonic Surface resonance Scientific coordinator: Dominique Legrand  Material: Biaccore 3000  Users: IFR: 70%, UMR 8576, FRE, UMR, external academics: 10 %, Industrials: 20% RMN and tray of structural glycobiology Scientific coordinator: Guy Lippens  Material: Spectrometers RMN Bruker  Users: IFR: ERI 8, FRE, UMR 8576, external academics (IBL, IPL, INRA, CNRS/Montpellier), industrials (Aventis)

Main assets for ONCOLille  High qualified engineers in charge of each component of the platform, with a specific and dedicated management team to control the access, work on equipment financing, conduct users  A strong activity in cross-disciplinary research, and a strong link with cancer biology The platform will provide a useful tool to the integrated programs of ONCOLille, for example to identify cell determinants and signalling pathways involved in resistance or to characterize specific factors associated with tumour dormancy in experimental melanoma.

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Peptide chemistry systems Chemistr y

Management and contact

H N

HN O O N H

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H2N

NH S

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System s Biolog y

 Dr Oleg Melnick – Institut de Biologie de Lille +33 3 20 87 12 14 [email protected] Location  Institut de Biologie de Lille, 1 rue du Pr Calmette- 59000 Lille

Key figures / Key features The originality of this platform is to combine 3 complementary areas of expertise:  the peptide and ligation chemistry,  the design and use of peptide-based systems such as microarrays  the design of cellular/biochemical assays related to signal transduction by RTKs.

Team involved in ONCOLille UMR 8161 CNRS, Oleg Melnick, Jerôme Vicogne,

Description (skills & resources) Team: 1 Research director, 1 engineer, 2 technicians. Equipments (a precise description of the equipment and fields of expertise can be found at the following address : http://csb.ibl.fr)  AlphaScreen® and Biacore® 2000 detection systems for studying binding between two purified molecules in solution or for quantifying signalling pathways on cell lysates.  MALDI-TOF and one analytical LC-MS systems for the characterization of molecules by mass spectrometry  Two peptide synthesizers, six preparative or analytical HPLCs, one preparative LC-MS system, one capillary electrophoresis system, two lyophilizators, one glove box for peptide or protein total synthesis  Three microarrayers (one non-contact piezoelectric, two contact system) and one microarray fluorescence scanner (Tecan) for microarray production and reading Scientific expertise: in Peptide chemistry, protein total synthesis and in surface chemistry applied to micronanosystems. Application domains: Protein total synthesis, peptide synthesis, epitope mapping, characterization / detection of antibodies, peptide / protein or protein / protein interactions, biochemical or phenotypic cellular assays related to RTK signalling.

Main assets for ONCOLille  A strong activity in cross-disciplinary research  A strong link with cancer biology with innovative translational approach  Particularly, for ONCOLille, the platform will provide innovative approach to take part in a bi-disciplinary project on HGF/MET signalling with two sections consisting respectively of : - a study of MET signal transduction leading to biological responses - the design of novel cancer strategies targeting the MET tyrosine kinase receptor and heparanase.

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Biotherapy platform Management and contact

Pr Francois Pattou +33 3 20 44 42 73 [email protected] Location  University of Lille II, Faculty of Medicine 1 Place Verdun 59045 Lille

Key figures / Key features The biotherapy platform, which belongs to the Institute of Predictive Medicine and Therapeutic Research (IMPRT – IFR114), is strictly reserved for the preparation and production of human cells for therapeutic purposes. The goal of this platform is to provide the best environment to develop new clinical protocols in biotherapy.

Team involved in ONCOLille UMR INSERM 837, E4

Description (skills & resources) The biotherapy platform, dedicated to the production of cells for clinical trials, is currently involved in three cellular therapy projects in the field of diabetes, cancer and cardiovascular diseases. The biotherapy platform consists of premises divided into two atmosphere-controlled work zones:  R & D zone for teams starting a protocol. This zone contains an ISO 7 clean rooms used for developing procedures and protocols that will subsequently be examined by AFSSAPS. Research teams who wish to use the biotherapy platform must submit a clinical protocol to the scientific committee, made up of clinicians and scientists.  clinical zone (ISO classes 6 to 8 clean rooms) which comprises - 3 clean rooms: Each room is equipped for the production of cells for therapeutic purposes (microbiological safety cabinets, incubators with C02 supply, centrifuges, lab bench consumables, microscope, vacuum inlet…). The equipment provided for the teams meets the standards and controls set by AFSSAPS (only teams who have official authorization to begin a clinical protocol are allowed access to the clinical zone). The biotherapy platform also complies with the specifications laid down by the Environment office of Lille Regional University Hospital (CHRU), which inspects the facility each year. The equipment provided in the clinical zone comprises: - wash room, consumables store room and room dedicated to cellular storage. Specialist biotherapy technicians maintain the facility. These staff members are directly involved in the clinical protocols, thus providing technical knowledge and assistance. The platform is closely located to the university hospital providing the availability of human cells with all ethical rules and to the Inserm units allowing the development of translational research programs.

Main assets for ONCOLille  The platform gives the opportunity to translate research programs from the laboratory to the clinic.  Free access based on specific project  A strong activity in translational medicine Specific contribution for ONCOLille: Laurent Mortier, Dermatologist at the Dermatology Department of CHRU Lille is conducting a phase I/II clinical trial of immunotherapy in metastatic melanoma to improve the efficacy of immunotherapy derived from dendritic cells. The autologous dendritic cells are produced at the biotherapy Platform by Philippe Marchetti’s group (Inserm U837-E4).

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II.3.3. INTEGRATED PLATFORM 2: IMAGING

Biophotonic In vitro Imaging Cellular Model

Functional Imaging

Molecular Imaging

In vivo Imaging Patients

Ex vivo Imaging Biopsies

Animal Imaging In vivo Imaging

Model Animals

ONCOLille Imaging platform (OIP) is based on integrative already imaging platforms and research teams devoted to in vivo imaging combining MRI, PET/MRI, PET/CT, a biophotonic platform labelled as an Equipex and molecular imaging using mass spectrometry imaging technology for ex vivo molecular imaging. This is the first time that in vivo, ex vivo, biophotonic and molecular MSI technology are combined in a same platform and devoted to cancer pathologies. OIP will offer a high added value in both clinical aspects of the resistance to treatment or dormancy on cancer but also in a fundamental aspect by understanding the molecular pattern of the biomolecules involved in course of diseases progression, resistance and dormancy. Such imaging technologies integration will make the OIP a highly interdisciplinary structure offering translation from technological and methodological developments to biological and clinical applications. 

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By integrating Mass Spectrometry Imaging (MSI) and biophotonic OIP open the door of fundamental research for physiopathological mechanisms understanding by tracking known compounds or looking to the discovery of new markers. It is clear that identification of new markers of pathology will give access to better understanding of signalling pathways and will be useful for defining new therapeutic targets and thus find new treatments. By combining MSI, biophotonic, in vivo imaging technologies and pathological platform OIP will give access to a better clinical diagnosis and prognosis, a better patient following with a clear objective at least a better care of patients and to shift to a medical personalized.


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In this context, two projects within the framework large program calls for ten years investment launch by French government have been proposed and will integrate the OIP if accepted i.e. EQUIPEX SPIDER MASS and Infrastructure MI2 project complementary to the EQUIPEX ImagInEx BioMed and SMART. 

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SPIDER MASS is dedicated to promote the development of a new MS instrument for translation of MSI from on tissue section ex vivo imaging to in vivo real time imaging for patients directly in the operating room. In fact, this new instrument will be based on the use of laser fibers to promote tissue ablation with subsequent analysis using MS. SPIDER MASS will aim in allowing for diagnosis of a suspected tumour to be performed with minimal damage to the patient. This would also give access to subsequent treatment by the same fibers using Photodynamic Therapies (PDT) to destroy only the volume of tissue that corresponds to cancerous cells or cells already changing phenotypes. MI2 will be a national infrastructure that aims to integrate the analytical capabilities of molecular imaging mass spectrometry (IMS), data validation by histology, bioinformatics treatment of high-speed data that are generated to increase knowledge of physiology and human diseases and contribute very significantly to progress in the field of health. It will gather the four major national players in the field of ISM, each leading a highly complementary techniques currently used (MALDI, SIMS and LA-ICP), 2 platforms and a histopathology laboratory already heavily engaged in the collection, analysis, processing and visualization of multimodal data.

ImagInEx BioMed project aims to establish a set of microscopic high-throughput screening and analysis of very high resolution. This platform will allow identification of new therapeutic targets and drug development faster, whose action on many diseases can be tested simultaneously SMART (Multiple Acquisition in Resonance and Tomography) EQUIPEX aims to reinforce multimodality functional imaging at Lille hospital. The acquisition of a new PET/MRI machine will provide answers to physiological and physiopathological questions which cannot currently be answered, thanks to the specificity of this new instrument for the simultaneous acquisition of functional data from two modalities. This project includes industrial collaborations: Siemens for the clinical research on a larger scale, particularly with partnerships with the Munich and Tübingen teams, as well as for the methodological research on protocols for the simultaneous acquisition of PET and MRI data and Aquilab for the quality controls in medical imaging. In the field of oncology, this instrument will be use to explore different organs or pathologies such as prostate, liver, head and neck tumours. SIRIC Imaging platform have two main objectives : 

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to offer a strong support based on a large platform of multimodal imaging including various types of instrumentations and excellent scientific background for helping in the objectives fixed for the two research programs to develop new methodologies and technologies in order to provide new cutting-edge technologies for fundamental and clinical research and ultimately for patients opening towards personalized medicine.

All the available technologies form together a highly integrative workflow with translation from fundamental research to patient‟s bedside applied from cellular models up to patients through small and medium size models of different cancer pathologies in order to provide highly valuable data on morphology and anatomy at various scales ranging from nm up to mm scale for cell organs, cells and tissues or molecular data on targeted compounds localization or

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looking for new regulated molecules and therapeutic targets as well as to understand action mechanisms of drugs. The general idea is to provide a platform starting from evaluation of patients using functional imaging to highlight cohorts with resistance to treatments and enter the workflow to come back to the patient with a solution that will be personalized according patient background (genetic, epigenetic, environmental & social factors). This comprehensive imaging platform includes state of the art equipments in medical imaging (see later) at the CHRU and at the COL and in radiation Oncology at the COL. The radiation Oncology Department at the Centre Oscar Lambret is a leading Department in France and Europe with its equipment and collaboration programs with international colleagues and manufacturers. The clinical and technological developments are at the forefront of the research in radiation oncology in Europe around stereotactic and IGRT/IMRT treatments. Recent developments have been performed in adaptive radiotherapy for head and neck and gynaecological tumours. A national program, headed in Lille, is starting to validate the impact of modern technologies (IGRT/IMRT) in treatment of aging women. Collaboration is starting with colleagues from Bruxelles and Leuven for considering the implementation of protons beams in clinical research and care (paediatrics, brain, prostate...).

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Cell Imaging and cytometry (Platform BICEL, IBiSA) Management and contact

Dr F. Lafont, Tel: +33 (0) 3.20.87.11.36 http://www.bicel.org/ Location  Bioimaging Center Lille-Nord de France, IBL, 1 rue du Prof Calmette, 59021 Lille

Key figures / Key features BICeL platform is a highly competitive platform member of the national infrastructure (GIS-IBiSA) and selected for the National Programme of investments for the Furure (PIA-EquipEx). BICeL mainly dedicated to high resolution analysis and dynamic molecular interactions mapping. It offers therefore a broad range of applications for clinical studies and is perfectly well suited for studying cancer diseases. BiCel offer an original platform for screening using microscopy of active compounds with therapeutic vocation, vaccines as well as multi parametric screening of gene expression extinction on cellular dosage.

Team involved in ONCOLille  CNRS UMR 8161, Institut Pasteur de Lille, University of Lille North of France  USR 3078 Institut de Recherche Interdisciplinaire, University Lille 1, University of Lille North of France  Centre de Recherche JP Aubert, Institut de Recherche sur le Cancer IRC, University of Lille North of France

Description (skills & resources) BICel gathers human resources and equipments from three sites: Lille University for Sciences and Technologies (IFR 147), CHRU (IFR 114) and the Institut Pasteur de Lille (IFR 142). The Facility is organised with a general manager and 5 departments including a highly qualified staff for each. Its development has been original and based on technologies not existing elsewhere in France, e.g. AFM (atomic force microscopy) couped to superresolution biophotnic methods, specific multimodal imaging systems. BICel provides services in all fields of microscopy: near field, electron, photonic and in flow cytometry. BICel is involved in many oncology projects (U800, calcium imaging in oncology, Oscar Lambret Centre, U837, signalling and cancer, University of Lille 1, oncology, CHRU). It also routinely proposes dynamic imaging strategies and interactions of the living (multiphoton, FRAP, FRET, FLIM, FCS, AFM, TIRF, PALM/STORM, STED), cell and molecular biology resources and infrastructures in order to adapter labelling with techniques of FRET, FCS, FRAP, photo-activation, … as well as infrastructures S2 and S3 on the Pasteur campus to conduct work requiring observations in vivo in a confined environment. BICeL is an important partner of several local and international companies (Leica Microsystems, Nikon, Osyris, Veeco, Zeiss, Roquette, Saint Louis Sucre, DIAGAST, NOVEON).

Main assets for ONCOLille BICeL Facility will be used to image with high resolution known molecules which are key players of carcinogenesis mechanisms and follow the distribution at the subcellular level of this compounds. Various imaging can be used in order to obtain information on molecules interaction or to study membrane properties of cells of different phenotypes such as normal and cancerous cells or resistance cancerous cells. High-throughput screening and high-content analysis will be performed in the context of prostate cancer.

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Molecular Imaging Management & contact

FOURNIER Isabelle, Professor, Tel: +33 320 434 194 ; FAX : +33 320 434 054 [email protected] Location  Bât SN3, University Lille 1, F-59655 Villeneuve d’Ascq Cedex l

 http://www.maldi-imaging.com

Key figures / Key features Molecular imaging platform is a multi and transdisciplinary platform with translational research from clinics to fundamental research aiming in identifying new markers of carcinogenesis mechanisms, tracking known markers, following distribution of drugs and corresponding metabolites (DMPK, ADME studies).

Team involved in ONCOLille    

Fundamental & Applied Biological Mass Spectrometry, EA 4550 (Pr. I. Fournier) Pathology Institute, Lille Hospital, C2RC (Pr. M-C. Copin) Gynecologic Clinic, Lille Hospital (Pr. D. Vinatier) Gynecologic Service, Centre Oscar Lambret (Pr. E. Leblanc)

Description (skills & resources) The MALDI Imaging Team (MIT) from FABMS laboratory is one of the world leaders in the field of a new emerging cutting-edge technology which is MALDI Mass Spectrometry Imaging (MALDI MSI). MIT was the first in Europe to have introduced and developed this novel technology in 2002 and was initiated in 2004 with a national Starting grant (ACI Jeunes Chercheurs) obtained by Dr. I. Fournier. Since 2004 the team had shown is expertise in the field of MALDI Mass Spectrometry Imaging and is now recognized as a major player in the international community. From MIT has emerged in 2009 a start-up, IMABIOTECH SAS located at Eurasanté, Lille, dedicated to MALDI MSI of drug. MIT is working since several years in close relation with gynecologic clinicians from Lille Hospital and Centre Oscar Lambert for ovarian cancer where MSI has proven is interest to identify new markers of these carcinomas giving further insights on the role of immune tolerance in the pathology. Many resources are available for Molecular imaging this includes the scientific knowledge on various aspects that are clinics, pathology, basic research as well as equipment resources. This include all instruments for pathology studies (robots for histology or IHC) and large equipments for Mass Spectrometry Imaging namely 3 mass spectrometers (MALDI-TOF/TOF Ultraflex II Bruker Daltonics, MALDI-LTQ orbitrap XL Thermo Fischer and ESI-IT Esquire HCD Ultra Bruker Daltonics), 2 deposition devices (ImagePrep microsprayer Bruker Daltonics, CHIP 1000 microspotter Shimadzu), 1 nanoLC (Ultimate Dionex), 1 micro extraction microfluidic nanoESI system (LESA Triverda Nanomate ADVION) plus dedicated bioinformatics tools.

Main assets for ONCOLille Molecular imaging is perfectly well suited for application in oncology. It will be used as an integrated tool for studying different aspects of resistance, relapse and dormancy. Molecular imaging using cross-validation in between histology and Mass Spectrometry Imaging (MSI) can be used to follow at the cellular level specific known molecules suspected to have an important role in resistance, relapse and dormancy. On another side it can also be used as a discovering tool for determining variation in molecular composition (metabolites, lipids, peptides and proteins) and identifying key factors of mechanisms using as basic knowledge to better understand signalling pathways underlined by the regulation of these factors. Moreover, MSI can be used to study the distribution of new therapeutics or to study action mechanisms of specifics treatments. At longer term MSI is to be developed for in vivo imaging as a diagnosis tool for patients.

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Medical Imaging Management and contact

Pr Damien Huglo  Tel : +33 3 20 44 67 93 / Fax : +33 + 20 44 47 88  [email protected]

Location  Nuclear Medicine, Hospital Huriez, CHRU of Lille, 59037 Lille

Key figures / Key features Medical imaging is available on both sites of C2RC, the Lille University Hospital and the Centre Oscar Lambret. Both sites own several instruments, of high performances and complementary. The imaging facilities include the Nuclear Medicine Departments and the Radiology Departments. The main objectives of these groups are to identify the best imaging markers for early diagnosis of cancer and its staging and to identify specific tools for post-treatment follow-up.

Team involved in ONCOLille       

Nuclear Medicine Clinic, Lille University Hospital (Pr Franck Semah) Radiology Clinic, Lille University Hospital (Pr Jean-Pierre Pruvo) Nuclear Medicine Department, Centre Oscar Lambret (Dr Philippe Carpentier) Radiology Department, Centre Oscar Lambret (Dr Luc Ceugnart) Radiation Oncology, Centre Oscar Lambret (Pr Eric Lartigau) INSERM U703 "interventional therapies Assisted by Image and Simulation" (Dr Serge Mordon) Clinical Departments of Lille University Hospital and Centre Oscar Lambret

Description (skills & resources) Each main building of Lille University Hospital and Centre Oscar Lambret own its radiology site. There are also 3 nuclear medicine sites located at Hospital Huriez, Hospital Salengro and Centre Oscar Lambret. The medical imaging platform includes 7 MR units (with a 3T MR Scanner dedicated exclusively to research work), 13 CT scanners, 9 angiography rooms and 28 ultrasound machines in the Radiology Departments and 8 gamma Cameras (all SPECT including 3 SPECT-CT) and 2 recent PET-CT systems GEMS) located in the Nuclear Medicine Departments. The forthcoming commissioning of a cyclotron on the Lille University Hospital site will provide PET tracers for biomedical research. All structures have a PACS and the communication between Lille University Hospital and Centre Oscar Lambret systems is planned. A clinical PET-MRI machine is asked in the Equipex program (SMART project).

Main assets for ONCOLille  Complete and recent medical imaging platform with some equipments dedicated to research work  Important and regional patient recruitment with strong expertise from imagers in specific domains  Strong collaborations between clinical physicians, researchers on treatments based on dynamic phototherapy (PDT) or laser thermotherapy (LITT), radiotherapy or surgery and imagers in a lot of fields of oncology (urology, haematology…)  Important connections between methodological (acquisition, segmentation, integration of PET and MRI anatomical and functional information …) and clinical projects.

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Animal Imaging (IMPRT) Management and contact  Pr Damien HUGLO  Tel : +33 3 20 44 67 93 / Fax : +33 + 20 44 47 88  [email protected]

Contact  Faculty of Medicine, Research sector, University of Lille 2, 1 place of Verdun, 59000 Lille

Key figures / Key features The in vivo Imaging facility is one of facilities of the Institute for Predictive Medicine and Therapeutic Research (IMPRT) created in 2000 and accredited as a Federative Research Institute (IFR 114) in 2002. This facility includes a platform dedicated for animals and especially for small animals.

Team involved in ONCOLille      

IFR 114, IMPRT, in vivo imaging platform, small animals (Pr Damien Huglo) IFR 114 IMPRT University Hospital Experimental Research (Dr Thomas Hubert) INSERM U703 "interventional therapies Assisted by Image and Simulation" (Dr Serge Mordon) Urology Department, University Hospital Lille (Pr Arnaud Villers) Radiology and Medical Imaging Department, , University Hospital Lille (Pr Laurent Lemaitre, Dr Philippe Puech) Nuclear Medicine Department, , University Hospital Lille (Pr Damien Huglo)

Description (skills & resources)  a 0.2T MRI machine dedicated to the investigation of large animal models (AIRIS Mate 0.2 T MR Scanner (Hitachi) specially pig and sheep with a special focus to MR interventional procedures  a 7.0T/20 cm horizontal magnet MRI system for the investigation of rodent models (Biospec, Bruker, Ettlingen, Germany), with a gradient slope of 400mT/m. For brain imaging, two separate radiofrequency coils are used : one Bruker 72mm inner diameter volumic emitting coil which the animal bed is inserted and one Bruker surface reception positioned to the top of the animal skull. For body imaging, only one coil allows the emission on reception of signal.  a preclinical PET/CT (Inveon multimodality, Siemens Molecular Solutions, Knoxville, USA) for rodents. The maximum field of view (FOV) is 5.5 cm x 8.4 cm for CT and its theoretical maximum special resolution of 30 µm. The PET is based on LSO elements (25,600) and 64 detector blocks. The detector diameter is 16.1 cm and the transaxial active FOV equal to 10 cm. The resolution at centre of FOV is less than 1.4 mm.

Main assets for ONCOLille This in vivo Imaging facility is not dedicated for oncology but perfectly suited for this and particularly in the field of resistance and relapse. Some studies were already performed for evaluated new minimally invasive therapies, laser interstitial thermotherapy (LITT) and photodynamic therapy (PDT) locally developed. For this, the rat prostate cancer model was used (with MRI and fluorocholine-for PET/CT) but this can be extended in other animal cancer models or other radiopharmaceuticals (FDG,…) and different studies are planned with different tumour models (melanoma…).

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Academic Radiotherapy Department – Centre Oscar Lambret Management and contact

Pr E. Lartigau, MD, PhD  Tel: +33 3 20 29 55 95  [email protected]

Location  Centre Oscar Lambret, 3 rue Combemale, 59 000, Lille

Key figures / Key features The Academic radiation Oncology department is one of the largest in France, implementing routine IMRT techniques and stereotactic brain and body treatments. Each year, more than 3000 patients are treated on the various machines and 550 brachytherapy procedures are performed. Contacts are ongoing with proton manufacturers (Still River, IBa…) to set up a proton facility within 5 to 7 years. It is the European training Centre for Accuray Inc. (Tomotherapy & CyberKnife).

Team involved in ONCOLille Physicians: Pr E Lartigau, Pr P Nickers, Dr X Mirabel, Dr L Schiappacasse, Dr B Coche-Dequéant, Dr B Prevost. Physicists : T Lacornerie, T Sarrazin, N Reynaert, A Wagner, F Dubus, N Crop

Description (skills & resources)       

CyberKnife, Tomotherapy Hi Art (2), Primus, Clinac 23X (2) Leksell gamma knife Simulation : Oldelft Simulix, Toshiba Aquilon MRI : General Electric 3T R&V :Nucletron Visir 2.0 Techniques :TBI, brain and body stereotaxy, multimodal fusion, gating Brachytherapy :LDR, PDR (3), HDR, Iodine 125

Main assets for ONCOLille Radiation Oncology plays a key role in loco regional treatments combined to surgery and /or chemotherapytarget treatments. The development of new models (IMRT, sterotaxy) has been largely implemented, making the Department able to cover all patient needs in the fields of daily treatments and clinical research. Specific programs are planned in ONCOLille project around adaptive radiotherapy in Head and Neck and Gynaecological tumours and the development of Monte Carlo algorithms for dosimetry.

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II.3.4. INTEGRATED PLATFORM 3: ANIMAL MODELS

Four sites are collaborating in the animal model platform of the SIRIC:    

IMPRT experimental animal resources platform Tumour model platform of Institut Pasteur Oncovet (see chapter I.2, page 30) O.C.R. (Oncovet Clinical Research)

Each site complements other‟s activities in terms of studied animals (experimental animals, including genetically modified mouse models vs. pets from private owners), tumour models (induced vs. spontaneous) and available resources (personnel, scientific expertise, imaging and treatment facilities on genetically modified mouse models). Regarding first scientific program on tumour and host-resistance to loco-regional treatments, a surgical suite and radiation therapy unit are available at Oncovet for loco-regional treatments of cancers. A specifically dedicated team of veterinary specialists will provide standard of care treatment to dogs with spontaneously arising cancers. Along with previously published datas regarding response to treatment and tumour and host related resistance, this highly skilled team will provide additional data and tissue samples for the identification of key factors identified in both other models and human tumours. O.C.R. tumour tissue bank will be open to experimental animal facilities to study tumours that have failed to respond to loco-regional treatment in canine patients. The main connection is to investigate and identify physio-pathological processes in experimental rodents then subsequently confirms that these mechanisms occur in dogs spontaneously affected by cancers. Tumour tissue bank gathered in dogs could be used for the establishment of xenograft models of canine tumours in mice, for experimental validation

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of canine models. For this evaluation, experimental and clinical structure will share their common resources (with complete technical structure for both diagnostic imaging and treatment) and expertise, for the selection of the most relevant models. The Institut Pasteur structure could then established mice model of tumour xenograft from tissue bank gathered in dogs. Evaluation of therapeutic candidate in xenograft model could be later translated to spontaneous tumour in dogs, in order to propose a more pertinent model of spontaneously occurring tumour for preclinical evaluation of diagnostic and therapeutic candidates. The clinical evaluation will be performed in Oncovet but will be supervised by OCR (with specifically dedicated team skilled in monitoring veterinary studies), to propose a methodological and technical supervision similar to clinical phase 1 and 2 study. Datas emerging from these studies will therefore be of high scientific value (as highly pertinent and validated models will be used) and will be ethically indisputable (as animal with spontaneously arising tumours will be treated with standards of care and innovative therapeutics procedures). Regarding second scientific program on tumour dormancy and immunoevasion, available mouse and dog models will be shared to identify the most relevant model for each tumour type. Tumour dormancy biomarkers will be identified in either of the previous models then validated in the other model. The main connection is to evaluate candidate drug efficacy on tumour dormancy in pre-clinical rodent model then establish proof-of-concept via clinical studies in dogs spontaneously affected by cancers. Again, data of high scientific value could be gathered at the Oncovet centre thanks to the methodological an technical support of OCR. These studies will bring valuables data on both efficiency and long and short-term toxicity of candidate therapeutic products proposed.

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Preclinical rodent tumour models : IMPRT and Institut Pasteur de Lille Two equipments for animal housing Researchers have access to two equipements of animal housing which are operational and in close connection.  The first is located in the CHRU site within the IMPRT  The second is on the Pasteur Campus, close to the Institut de Biologie de Lille. Common teaching user sessions are organized: one session per year for legal training in animal care level 1 and 2. The IMPRT platform is completed with an effective tray of animal imaging. These facilities are accessible to all teams of the Lille scientific community. Skills and resources of both facilities are described in the two following sheets

Team involved in ONCOLille, for both equipments Inserm U837 (Team 3, 4 and 5), UMR 8161 CNRS, Inserm U1003

Main assets for ONCOLille  A highly-qualified Staff (A Scientific Supervisor in charge of the management of the platform and a technician devoted to histological techniques). All the staff members have the full legal capacity in animal care and training in surgery.  Open access  Non-routine procedures, Protocol development  Access to a catalogue of models  Offers a service to researchers to perform customised projects  Derivation of lines, the maintenance of lines under SPF conditions  Histopathological analyses These platforms will be useful tools in the framework of ONCOLille projects:  Tumour and host resistance to loco-regional treatments IP-1 & 2:To study response to loco-regional treatments in spontaneous and induced animal models in developing animal models to determine physiopathological processes linked to primary or secondary tumour resistance (oesophageal cancer)  Tumour dormancy and immunoevasion with mouse model of tumour dormancy (Acute Myeloid Leukaemia), Tumour stem cells (prostate melanoma) and Tumour dormancy and senescence

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IMPRT - Experimental animal resources platform Management and contact

Thomas Hubert +33 (0)3 20 62 34 63 [email protected] Location  IMPRT, IFR 114, Place de Verdun, 59045 Lille cedex

Description (skills and resources) Equipment  Animal facility of the University-Hospital experimental resources department, director: Thomas Hubert: - Certification status: animals in open cages. - Large mammals (pigs, ewes), rodents (mice, rats), Lagomorpha (rabbits) - Available: operating rooms, micro-surgery station  High-tech animal facility (manager Delphine Taillieu, [email protected]) - SPF (specific pathogen free) status. - To maintain this status, animals are housed in cages individually ventilated, enabling transgenic and immunodeficient animals to be used.  Several areas: - Isolation techniques: to maintain nuclei of transgenic lines under elevated confinement - Breeding: to amplify reproducers and supply animals requested by users - Experimentation: to cage animals included in a protocol. Among the rooms available are: stereotaxis, metabolic studies, surgery, infusion/fixation, etc. - A2: to infect animals with pathogens

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Tumour model platform - Pasteur Institute of Lille Management and contact

Decavel Jean-Pierre +33 (0)3 20 87 79 50 [email protected] Location PHOTOPHOTO

 Institut Pasteur de Lille, 1 rue du Pr Calmette 59000Llille

Description (skills & resources) Animal resources  Mouse Embryo development - Provide mouse embryos at different stages between E 8.5 and D 3 after birth - Provide embryo tissues at different stages  Transgenic Models - Related to Mouse Development - Related to Cancer and Tumour Development  Cancer Models - Tumour graft - Tumour growth evaluation - Metastases development and evaluation - Mammary gland development - Mammary gland fat pad clearing The Animal Models Core Facility can provide access to core equipment and facilities as well as expertise for surgery or protocol development. Equipment  Animal surgery - Surgical stereo-dissecting microscope - Inhalant anaesthesia delivering system - Alzet mini-pumps implantation - Implantation of tumour or normal cells in mammary fat pad - Tissues collection  Tissue preparation and histology Animal perfusion - Tissue collection - Paraffin embedding unit - Microtome - Cryostat - Slides staining

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ONCOVET CLINICAL RESEARCH Management and contact

Dr Dominique. TIERNY – Director Dr I. Bemelmans, +33 (0)3 20 56 82 93 http://www.oncovet-clinical-research.com Location  Immeuble ONCOVET, Av Paul Langevin, 59650 Villeneuve d’Ascq

Key figures / Key features Oncovet Clinical Research (O.C.R.) is a private Contract Research Organization. Our objective is to propose validated animal models of spontaneous diseases. Recent medicine history highlighted the parallel between animal and human medicines. Pets and humans share common diseases with analog physiopathology. The private-owned dog can stand for a relevant model for various cancers: renal, cardiac or Central nervous System diseases. Founded in 2010, O.C.R. is a start-up with the “Jeune Entreprise Innovante” Label. The team is formed by 8 qualified experts including 2 PhDs.

Team involved in ONCOLille D. Tierny, A. Hidalgo, F. Serres, C. Robat, N. Granger, I. Bemelmans, C. Delcourte, L. Fanchon

Description (skills & resources) O.C.R. is specialized in the design, organisation, monitoring and reporting of GCP clinical studies on animals. More specifically:  Clinical science: O.C.R. has internal experts in oncology to select relevant animal models and define appropriate study designs according to best practices.  Regulatory: O.C.R. handles directly clinical trial dossier submission and interactions with French authorities (ANSES)  Clinical operations: O.C.R. manages the Clinical Record Form conception, investigator training, site monitoring, data review, statistical analyses and final study report writing O.C.R. has internal R&D programs focused on the validation of animal models. Fully validated models include: spinal cord injury, degenerative mitral valve disease, mammary tumours and melanomas. Internal laboratory capacities are available: histology, immunohistochemistry (IHC) managed by a certified pathologist. For oncology projects, tumours are collected, analysed and stored in a tissue bank to later identified specific targets of interest. A PhD project, in collaboration with IRCL (INSERM 837) started in 2011 on tumour dormancy. Team members :  Dr Dominique Tierny (DVM) is CEO and co-founder. She has more than 15 years of experience in clinical oncology. She acts as a project leader and scientific advisor in oncology.  Dr Antoine Hidalgo (DVM, MS) is Business developer and co-founder. He is a veterinary surgeon specialized in oncologic surgery. He acts as a scientific advisor in surgery.  Dr François Serres (DVM) is scientific advisor and co-founder. He is specialized in internal medicine and cardiology.. He is responsible for the identification and characterization of new relevant animal models.  Dr Ingrid Bemelmans (DVM, MS) is specialized in anatomic pathology. She previously worked in comparative pathology in the field of mammary tumours. She is responsible for model development and target identification.  Dr Cécilia Robat (DVM, Dip. ACVIM-Oncology) is a specialized oncologist. She worked in medical and comparative oncology at the University of Madison, WI. She acts as a scientific advisor in oncology.  Dr Nicolas Granger (DVM, MRCVS, Dip. ECVN) is a specialized neurologist. He has 10 years of experience in

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clinical and experimental neurology. He acts as a scientific advisor in neurology.  Dr Laurent Fanchon (DVM, PhD) is Head of Clinical Research and Regulatory Manager. He previously worked for animal health company where he conducted field trials in France and Europe.  Claire Delcoutre (MS, PhD student) is a PhD student and Clinical Research Associate. She started a PhD in 2011 on metastatic process and tumour dormancy.

Main assets for ONCOLille  Strong expertise in oncology: Dr D. Tierny has more than 15 years of experience and Dr C. Robat is a certified specialist in Oncology. Both of them have a clear interest in comparative oncology. Dr Bemelmans is a certified pathologist with a strong focus on mammary (breast) tumours.  Large access to animals with spontaneous (non-induced) tumours: animals and humans share the same environment, risk factors, and associated diseases  State of the art analytic platform: OCR has internal histological platform with a ventilated table for gross examination and formalin fixed tissue trimming; a microtome for paraffin-embedded tissue sectioning; and a Ventana automated stainer (Discovery XT) for immunohistochemical analysis using antibodies and immunohistochemical protocols especially adapted to canine and feline tissues. Tissue processing, paraffin embedding, sectioning and staining are outsourced with a private human pathology laboratory (Centre Nordpathologie).  Canine and feline tissue bank: after phenotypical analysis of tissues samples, OCR collects frozen tissue samples for molecular analysis relating to DNA, RNA and proteins. Tumour tissue, blood and when possible healthy tissues of the same animal are stored at -80°C.

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II.3.5. INTEGRATED PLATFORM 4: CLINICAL RESEARCH AND METHODOLOGY The aim of the Clinical Research and Methodology Platform is to accompany the project participants (scientific programs and/or other platforms) from the conception phase of the scientific project to the analysis and publication phases. To arrive at these goals, the platform comprises units which cover all the aspects of translational and biomedical research: 



 

2 Methodology and Biostatistics Units (MBU), one in the CHRU, another in the Centre O. Lambret. These 2 units provide methodological aid in the planning stage of the projects (experimental designs, primary endpoints…) as well as assistance in the statistical analysis of the data and the publication of results. Moreover, they develop, via the framework of the EA2694 research team, their own research topics within ONCOLille presented below. 2 Clinical Research Units, one in the CHRU and one in the COL, united together within the Clinical Research Centre (CRC) which is dedicated to the management of trials aiming to facilitate and accelerate the implementation of clinical research in accordance with Good Clinical Practice and regulatory issues. 1 unit dedicated to database-management, using professional tools and staff 1 unit dedicated to the management of registries (imperative in the research programs).

Methodology

Investigation, GCP, …

MBU

MBU

FRC

UIRC

(CHU)

(COL)

(CHU)

(COL)

EA 2694

See sheets n°1 & 2

Data-management & Registries

DPC

CR

CRC

See sheets n°3 & 4

See sheets n°5 &6

The 4 research axes of the Methodology and Biostatistics Units are the following: 1. Phase I clinical trial methodology for better patient selection and increased treatment efficiency: Better patient selection is crucial to treatment development since results will determine the best dose for future patients, especially in combination trials. Prognostic models using classification and regression tree (CART) approaches for predicting the risk of early death will be developed and implemented in trials so as to jeopardize neither the trial nor the future drug development process. In order to estimate both long-term tolerability and anti-tumour drug activity, the use of expanded cohorts in phase I trials is useful for evaluating the dynamics of tumour growth. This criterion will be defined on the basis of retrospective analyses of patients treated in different French Centres. 2. Phase II / III clinical trial methodology for optimizing treatment using criteria combining both efficacy and toxicity: Best treatment strategy decisions rely on efficacy and toxicity, yet these criteria are usually evaluated separately. This analysis is not optimal since it ignores competing risks. Statistical modelling for evaluating the joint distribution of safety and efficacy outcomes will be undertaken. A multi-dimensional parameter model including a weighted combination of toxicity and efficacy outcomes and the doses at which one, none or both occur will be

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developed. Simulations under different scenarios and weight functions will allow a comparison of different treatment strategies, especially for the evaluation of targeted therapy. Particular emphasis will be on multiparametric models in these specific cancers evaluating different endpoints such as survival adjusted for quality of life, incorporating human sciences parameters. 3. Developing innovative prognostic scoring systems applicable to optimisation of treatment strategies and followup: Prognostic scoring systems are now widely used for evaluating the severity of the disease before many treatment decisions. The EA2694 team has a strong experience in the development of state of the art prognostic scores in haematology (Waldenström, Acute Myeloid Leukaemia, Primary Myelofibrosis). We will develop similar scoring systems in other malignancies such as prostate, oesophagus and head and neck carcinomas with the aim to identify primary to the initiation of treatment, patients who will likely present features of chemoresistance or tumour dormancy. Another objective is to design prognostic models applicable during the follow-up of patients for predicting the risk of subsequent competing risks, taking initial and follow-up characteristics into account. 4. Developing new methods of “scan statistics” in order to identify clusters of excess or low cancer incidence: Detection of atypical geographical areas in terms of cancer incidence is an important problem in epidemiology of cancer disease. The aim of Scan statistic methods is to detect temporal and spatial clusters wherein the risk of cancer is higher (or lower) than in the rest of the studied area by using data from registries. EA2694 has been working for several years in this domain and we propose to apply this methodology in order to identify clusters of excessincidence or low-incidence of cancers in this project. In addition, we will develop original research in the field of scan statistics: (1) estimation of the scan statistics distribution; (2) error estimation in the p-value approximations; (3) assessment of the influence of the window frame on the approximation of the scan statistics distribution.

Regarding the Clinical Research Units, the CRC is based on the following  

"a single acces" for training in the use of administrative records, regulatory and logistical aspects for clinical trials taking place in the Lille site. a common functional platform for investigation and treatment of early phase trials involving the investigators, clinical research assistants CRA and nurses.

CRC organization includes:     

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Regular updates of GCP knowledge for all the investigators Consultations with an expert clinical research nurse before each inclusion Specific communication to the Genaral Practitioner to inform him/her of the trial objectives and potential treatment side effects Guarntee to the patients a privileged access to the common platform of molecular biology and imaging platform and functional imaging Provide to the clinical research organizations (CRO), academic cooperative groups and industrial partners involved, an active solicitation for access to early phase trials


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Methodology and Biostatistics Unit - CHRU Management and contact

Pr. Alain Duhamel – PU-PH, Director of MBU +33 3 20 44 55 18, [email protected] Location  CHRU Lille, EA2694 - University of Lille 2, 1, Av O. Lambret - 59800 Lille

Key figures / Key features The Methodology and Biostatistics Unit (MBU) of the Lille Universitary Hospital (CHRU) is a dedicated platform for the methodological and statistical aspects of research projects. It includes 6 biostatisticians, 1 Data manager, 2 epidemiologists and 1 assistant professor in Medical Informatics. MBU takes in charge every year nearly 70 new clinical research projects in the frame of this main activities :  the development of clinical research projects (design, objectives, primary endpoint, sample size, statistical analysis plan),  the data management of clinical databases, statistical analysis and the interpretation of results (statistical modeling, survival analysis, development of prognosis scores)  the participation to scientific publications. The Unit of Methodology and Biostatistics builds on skills of the research team EA2694 – "Public Health: Epidemiology and Quality of Care", which focuses on three topics:  Quality of care and methodologies in the fields of Biostatistics,  Medical Informatics and Health Economics,  Epidemiology of chronic diseases. EA2694 gathers 34 researchers, 7 engineers and 13 PHD students: epidemiologists, clinicians, and methodologists in the fields of biostatistics, medical informatics and health economics. Ranked A by the AERES in 2009, EA2694 has published 580 publications in international journals since 2000. Directed by Pr Alain Duhamel (index H= 32), it is the lead team for the PSIP project funded by the FP7 (2008-2011) and has obtained 5 grants from ANR and 6 PHRC (French Ministery of Health).

Team involved in ONCOLille The principal investigators involved in ONCOLille will be A Duhamel (Professor of Biostatistics PU-PH), managing the EA2694 team and the MBU, and working in the field of high dimensional analysis, knowledge data discovery from large databases and development of prognostic scores. He will be assisted by :  G Marot, assistant professor in biostatistics and expert in the interpretation of genomic data analysis using high dimensional analysis.  F Vasseur, assistant professor specialist in genetic epidemiology.  M Genin, doctoral scientist in the field of scan statistics for the detection of clusters of events. The engineers of the MBU (P Devos, J Salleron, S Pesin) will participate in the clinical studies developed in ONCOLille for the design, the data management and the statistical methodology.

Description (skills & resources) EA2694 and MBU have developed major advances in biostatistics concerning high dimensional analysis for longitudinal studies or genomic data, development of diagnostic or prognostic scores, scan statistics for the detection of clusters of events, handling of missing data and data mining techniques for the analysis of large data bases. Recently, the team has recruited a researcher specialized in cost effectiveness analysis which will contribute to ONCOLille.

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The expertise of EA2694 and MBU in the field of clinical/translational research (study design, data management, statistical analysis, scores development) is well-established. The team's members are strongly involved in clinical research at the Lille universitary hospital and they work with all clinical teams on the site, notably with oncologists, paediatricians, pneumologists and ICU physicians. All members of the MBU are equipped with especially dedicated hardware and software (SAS, Stata, R, Capture System ...) necessary for the conduct of research projects. The members of MBU have coauthored 287 publications in international journals since 2007 including papers in the New England Journal of Medicine, Lancet, Blood, CMAJ, Radiology, Gastroenterology, Critical Care Medicine, Neurology and J Clin Endocrinol Metab.

Main assets for ONCOLille The Methodology and Biostatistics Unit and the team EA2694 will participate in the clinical researches studies developed within ONCOLille via the “Methodology and Clinical Research” platform :  clinical validation of new biomarkers (biomarkers for the early diagnosis, biomarkers of severity of disease, predictive biomarkers of the disease evolution),  development of prognostic scores,  development and assessment of new drugs,  epidemiology of cancer diseases,  identification of spatial and space-time variations in incidence of cancers using scan statistics.

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Methodology and Biostatistics Unit (COL) Management and contact

Andrew Kramar – Biostatistical director  Tel: +33 3 20 29 58 93  [email protected]

Location  Centre Oscar Lambret, Lille

Key figures / Key features Key features concern research areas in bio statistical and computational issues that arise in the design, analysis and statistical modelling of clinical and preclinical studies. Methodological research concentrates on models for efficient designs for evaluating efficacy and safety endpoints in early phase clinical trials, especially combinations of cytotoxic and biological agents and radiotherapy. Analyses of recurrent and transient side effects of varying severity, with a special attention to radiotherapy late effects, is of particular interest as is quality of life and the modelling of multiple biomarkers as longitudinal data for the monitoring of response to treatment within a competing risks framework. The statistical challenges to multidimensionality problems of microarray analyses are another important research theme. Dr A. Kramar (H-index=30) has published 141 articles (36 since 2007, 41 as first or last author) covering many aspects of cancer research. About 30 statistical studies have been conducted within the past 5 years.

Team involved in ONCOLille     

EA 2694: translational and fundamental research MBU CHRU: study design, data analysis and publication of clinical trial results UIRC / FRC: regulatory, logistic, financial and organisational aspects of clinical trials Persons participating in the project: COL: Two research biostatisticians (PhD), two statisticians (MSc), 2 data-managers, and 1 data entry technician.

Description (skills & resources) All members of the unit are equipped with especially dedicated hardware and software (Clinsight, SAS, Stata, R,…) necessary for the conduct of research projects. Skills involve expertise in cancer clinical trials and biostatistics. A 400 page book co-authored by Dr A. Kramar entitled “Méthodes biostatistiques appliquées à la recherche clinique en cancérologie” has recently been published (Nov 2011), and reflects the large number of domains using statistical methods in cancer research.

Main assets for ONCOLille A close coordination with the Clinical Research Unit, especially academic sponsored trials as well as a coordinated accompaniment and a direct implication with the teams involved in the main programs and platforms of ONCOLille. Regular training of young statisticians and researchers allows an organisation of scientific meetings on statistical methods around common problems, especially new methodological developments. A guarantee that a well designed, well conducted and correctly analyzed research project will have a high impact in the scientific community as opposed to a poorly designed and incorrectly analyzed project which will not be convincing, will have a low impact and wasted resources both financial and medical.

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Clinical Research Unit of the CHRU – Federation of clinical research Management and contact

Christian Libersa, MD/PhD, Director of “Fédération de Recherche Clinique”, CHRU de Lille  [email protected]  tel: 0033. 3. 20.44.41.45

Location 

Bat USN B, Centre Hospitalier Régional, 59800 Lille

Key figures / Key features The « CHRU de Lille” has since fifteen years initiated a process to support translational research by creating a "Delegation to Clinical Research and Innovation "(DRCI) covering all aspects of biomedical research. In 2006, it created the Federation of Clinical Research (FRC) responsible of (1) the instruction and assistance in the preparation of clinical research projects sponsored by the establishment (2) the operational implementation of clinical research projects (academic and industrial) and their follow-up. Those activities are performed by specialized clinical research professionals in structures or platforms which support the investigation (CIC, CRB…). It provides analytical support, methodological support (in relation with the MBU) and logistical support and management of regulatory issues. It provides investigators the resources (Clinical Research Technicians) required for the investigational activity for the daily conduct of clinical studies. Concerning Oncology, the “CHRU de Lille” sponsored in 2010 24 studies (with 428 patients included in our establishment), was investigation centre in 298 studies (159 academic studies and 139 industrial studies) with 685 patients recruited.

Team involved in ONCOLille    

The Federation of Clinical Research The Clinical Investigation Centre: structure labelled by INSERM and dedicated in early phases The Biological Resource Centre: structure dedicated to the management of samples and biological collections The Technology Investigation Centre: structure labelled by INSERM and dedicated in evaluation of medical devices.

Description (skills & resources) The Federation of Clinical Research includes medical resources, administrative resources (secretaries, assistants...) and specialized resources in clinical research:  About 10 full-time clinical research associates (CRA)  About 70 full-time technicians of clinical research (TCR)  About 2.5 full-time about pharmacovigilance and quality assurance. These resources are changing depending on the number of projects undertaken within the institution. Currently, nearly 20 CRA/TCR are dedicated to research activity in Oncology, especially in haematology, digestive surgery or respiratory oncology.

Main assets for ONCOLille The Federation of Clinical Research has proven expertise in managing clinical trials (high annual number of projects), including oncology. As part of the project SIRIC, it will allow:  The guarantee of quality clinical research  A very useful assistance in the process of translational research

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Clinical Research Integrated Unit (UIRC) - COL Management & contact

Stéphanie CLISANT, PhD, [email protected] tel: 00 33.20.29.55.60 Location  Unité Intégrée de Recherche Clinique, 3 rue F. Combemale, 59020 Lille

Key figures / Key features The clinical research integrated Unit (UIRC) of the COL is dedicated to the management of trial aiming to facilitate and accelerate the implementation of clinical research in accordance with Good Clinical Practices.Since 2007, the Centre Oscar Lambret is one of the top five in terms of number of patients included in clinical research and one of the top 3 in terms of trials sponsorship among the French cancer centres. 706 patients were included in 158 clinical trials, representing more than 12% of active file of patients in 2010. Interestingly, the part of academic trials represents more than 80% of included patients. Studies conducted are principally phase I, II and III therapeutic studies of new molecules or therapeutic strategies with a particular focus on translational research. More than 20 trials are sponsored by the COL each year, recruiting 500 patients all over the country The development of these projects is carried out with the support of the Methodology and Biostatistics Unit st of the Centre, under the direction of Andrew Kramar since April 1 2010.

Team involved in ONCOLille The UIRC is divided into 2 sub-units: the first one is dedicated to management of investigational protocol sponsored by pharmaceutical industry and academic groups. The second one is dedicated to sponsoring activity. It provides methodological support, regulatory and logistic documentation for the development of projects planned by investigators of the Centre. As such, it centralises and also sponsors projects susceptible to enter into the scope of grant proposals from INCa (Institut National du Cancer), notably the PHRC and pharmaceutical industries.

Description (skills & resources) The UIRC disposes of a care unit with 8 beds and medical chairs specifically dedicated to taking care of adult cancer patients included in early phase clinical trials (phase 0, 1 or 2). The unit was conceived as an interdisciplinary platform dedicated to clinical and translational research. The staff of the investigation unit includes 3 full-time CRA and 7 full-time TRC (Clinical Research Technicians). Each CRA and each TRC is in charge of one or two cancer sites. One ARC is responsible for applying quality control procedures. The sponsorship unit comprises 2 ARC project leader and 2 ARC monitor and an assistant administrative trial manager. The projects are managed and conducted by a single organisation allowing a rapid implementation of the study (mean delay of 2 weeks after receipt of the CPP (Comités de Protection des Personnes) and AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé) authorisations, once the internal authorisations of the CEC (Commission des Etudes Cliniques) of the Centre have been obtained. This commission meets monthly and insures the scientific importance of each study in accordance with the strategic and political orientations of the Centre and its external scientific council. If necessary, extraordinary meetings of the CEC can be organised for rapid decisions depending on the importance of the proposed study.

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Main assets for ONCOLille Among all projects sponsored by the UIRC, a certain number already concern the pathologies mentioned by ONCOLille:  Rational pharmacological individual adaptation of doses of pemetrexed (Alimta) administered with cisplatin and vitamin supplementation in patients with a pleural mesothelioma  Morphological and molecular characterisation of head and neck tumour occurring in patients who have no risk factors for alcohol or tobacco or professional  Stereotactic irradiation for hepatocellular carcinoma: Phase II study  A multicentre randomized phase II study to evaluate the benefit of chemotherapy plus best supportive care (BSC) versus BSC in patients with metastatic oesophageal cancer (MOEC) of squamous-cell type (SC) (MOEC-SC) who have not experienced disease progression or unacceptable toxicity during a 2 monthcourse of chemotherapy The Unit will be an important platform for the development of new investigational projects and sponsored projects in the fields of ONCOLille: Furthermore, 4 projects are conducted in collaboration with the University of Lille 3 (Dr Véronique CHRISTOPHE), who convinced us of the importance to pursue and amplify this research in behavioural science coupled with clinical trials

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Canceropôle Nord Ouest Data Processing Centre (DPC) Management and contact

Michel Henry Amar, MD, PhD +33 231 455093 [email protected] Location  Canceropôle Nord Ouest, 2, avenue O. Lambret, 59000 Lille

Key figures / Key features The DPC conducts studies for (i) projects that have been assessed and funded by institutional organisations, funding agencies or charitable scientific organisations and foundations, and (ii) projects promoted and/or funded by the three comprehensive cancer centres in the four-region group, or by the scientific cooperation group run by the four university hospitals (insofar as they are part of a clear effort to structure research in the four-region group). Research projects focus on phase II and III clinical trials and on diagnostic, prognostic and epidemiological studies promoted by institutional organisations.

Team involved in ONCOLille The DPC team is composed of 1 director, epidemiologist, specialized in public health; 1 project leader, chemist; 1 biostatistician; 2 data managers; and 1 data operator (data entry and data processing). All of them are taking part in ONCOLille.

Description (skills & resources) The DPC team offers skills in data management of health data that concern clinical trials, diagnostic and prognostic studies as well as epidemiological studies. They can also provide advice and assistance in the study design, logistics, statistical analysis and publication of results. Resources include on-line data base management software which complies with the EMEA/FDA requirements regarding IT systems as well as electronic signature and various international norms. It can be accessed by authorized people through a highly secured system (VPN/SSL mode up to 128 bits; Transmitted data encrypted). Its web interface allows study management via standard data entry in client/server and/or via the Internet. Daily backup is made using two independent servers. Resources also include standard statistical and graphical software facilities. The DPC was certified by the French National Cancer Institute (INCa) in July 2007.

Main assets for ONCOLille The DPC represents an essential strategic and logistical tool in the development and the management of clinical and epidemiological studies to be sponsored and conducted within the SIRIC framework. The DPC can also be viewed as an opportunity for joint projects involving research teams in biology, humanities and social sciences and clinic.

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Cancer register of Lille and its area Management and contact

Dr Karine Ligier - Scientific coordinator  [email protected] / 0033 20 97 94 92

Location  Registre général des cancers de Lille et de sa région (GRPS/CRRC) 235 avenue de la Recherche - 59373 Loos cedex

Key figures / Key features The General Cancer Registry of Lille and its area was formally created in January 2009, and is integrated in the Regional Cancer Reference Centre Healthcare Cooperation Group (GCS – C2RC). Certified by the National Committee of Registries (InVS and Inserm) since November 2008, its missions are to:  Produce local cancer statistics, and participate in the production of regional cancer statistics, national and international  Assess the impact of public health measures  Develop studies on the care management of patients  Develop ethological studies on the determinants of the occurrence of cancer or the care management and survival of patients. The registry records the following tumours in the area of Lille (800 000 inhabitants):  invasive cancers  in situ cancers of the colon-rectum, breast, cervical, melanoma  ovarian tumours "borderline"  tumours benign or of uncertain for the bladder and central nervous system. The data are collected from 35 sources (pathology and biology laboratories, hospital, health insurance…)

Team involved in ONCOLille The team is composed of a chief scientist two epidemiologists and investigators, a data manager, five clinical research assistants and a secretary, who will participate to the SIRIC project

Description (skills & resources) Currently, the General Cancer Registry of Lille (800,000 inhabitants) is collecting data on patient ages and addresses, incidence dates, and cancer topography, morphology, and size. Incidence data for 2005 and 2008 are available on the website of the registry: www.registrecancers59.fr. These data show that there is strong excess- incidence of cancers related to tobacco +/- alcohol (UADT, oesophagus, lung, and bladder) compared to the national incidence. Some medical data, such as the stage of cancer at diagnosis or the modality of diagnosis could be collected. So, we manage or participate in epidemiological research concerning descriptive epidemiology of care management and survival of patients with head and neck cancers, prostate cancers and patients with sarcoma.

Main assets for ONCOLille Thus, additional surveys will be conducted to supplement the information already collected by the Registry. For this purpose, field-specific studies (epidemiology, biology, genetic, psychology, informational sciences, economic…) will help to explore occurrence, management care, late diagnosis and survival of patient with cancer issued of the general population (i.e. unbiased recruitment).

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III.

Integrated research programs

III.1. Overview of the two integrated programs ONCOLille will develop an original project aiming to achieve state of the art integrated research in some of the most important issues for oncology: tumour resistance and persistence after loco-regional treatments. ONCOLille will develop two major programs:  

Program 1 will focus on tumour and host resistance to loco regional treatments and on the understanding of late diagnosis and socio economical resistances to enter medical care. Program 2 will be dedicated to tumour dormancy and persistence and on the modelling of tumour recurrence and patients reinsertion

Program 1 will have a primary objective to identify the key-determinants for resistance to locoregional treatments. For this, 5 research axes are proposed:     

1- To identify cell determinants and signalling pathways involved in resistance in order to develop new biomarkers and dedicated targets 2- To evaluate new imaging tools for early diagnosis and follow-up after loco-regional treatments 3- To study response to loco-regional treatments in spontaneous and induced animal models 4- To develop diagnostic and therapeutic clinical approaches to decrease the tumour and host trend for resistance 5- To strengthen the access to care and reduce treatment delays, that may strongly influence host (and probably tumour) resistance

Two emerging programs will be developed (see Chap III.3.4):  

To improve efficiency in loco-regional radiotherapy treatment, with the development of a transversal Monte-Carlo dose engine To model morbi-mortality of primary liver cancer in France across various stages of severity: evaluation of different strategies according to the amount of screening and therapeutic resources.

Program 2 will have a primary objective to understand recurrence. The program will specifically focus on mechanisms contributing to tumour dormancy and relapse after a period of complete remission. With specific goals:    

1- To create new experimental models of tumour dormancy. 2- To understand basic mechanisms of tumour dormancy 3- To identify new predictive factors of relapse and translate them into the clinic 4- To develop new drugs able to target dormant tumour cells and avoid or delay relapse.

Two emerging program will be developed:  To model treatment follow up  To adapt socio professional reinsertion Based on a large number of clinical and fundamental research programs and on the existing level of excellence, the project has the originality to stand on very strong basic or clinical research and to be able to achieve significant breakthroughs in the modelling of resistance to

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initial treatment and recurrence after treatment for the benefit of patients and healthcare providers. All programs will integrate biological research, translational research, innovative imaging, clinical research and humans sciences developments, particularly in the field of comprehensive handling of the disease for the patient and the family (global care). Dissemination of knowledge will be directed towards patients in the field of adapted follow up and professional reinsertion, as well as towards general practitioners and political authorities. The consortium ONCOLille will bring new data on the mechanisms of resistance and persistence to treatment in human tumours. Bringing together such information in biological models, imaging and clinical research will help to drive new studies in the field of adaptive and personalised medicine. Due to the specific cancer incidence in our region, this proposal has clinical reality. Based on the past 5 years‟ history of integrated research, together with the involvement of all players in cancer care and strong political commitment, our project provides a real opportunity to implement a truly comprehensive cancer centre in north of France.

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III.2. Tumour and host resistance to loco-regional treatments Program 1 coordinator: Pr. Christophe Mariette, MD, PhD, Clinical Department of Oncological surgery, Inserm research team U837-E5 “Mucins, epithelial differentiation and carcinogenesis”, University Hospital of Lille and Lille 2 University [email protected]

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III.2.1. MAJOR THEME OF THE PROGRAM III.2.1.1. MEDICAL RATIONALE AND SCIENTIFIC OBJECTIVES OF THE PROGRAM Head and neck, oesophageal, gastric, primary liver, lung and mesothelioma cancers are still of poor prognosis despite increasing efforts to optimize therapeutic strategies toward a better locoregional and systemic disease control. Despite aggressive therapeutic strategies combining frequently, in the post and/or in the preoperative settings, surgery, chemoembolization, radiofrequency, radiotherapy and chemotherapy, most of the treated patients will experience persistence disease due to treatment resistance ; the causes of which are numerous and need to be better understood. Consequently, the researchers of this Program seek to identify key factors which are linked to tumour and host resistance to loco-regional treatments. We propose a comprehensive integrated research program that explores these factors using complementary approaches: identification of biological paradigms explaining resistance, animal bearing tumour models, modern imaging techniques explorations, and identification of social and compartemental determinants. This integrated research will be backed onto an important activity in clinical and surgical research dealing with the impact of loco-regional treatments for head and neck, oesogastric, primary liver, lung and mesothelioma cancers. This Program integrates experienced and internationally known physicians (numerous grants and high level publications), high-level researchers (A+/A AERES), and numerous industrial partnerships towards a patient-specific diagnosis and treatment for those targeted cancers. Within this overall aim, each team brings to this Program complementary expertise and approaches. The primary objective of the research program is to identify the key-determinants for resistance to loco-regional treatments. For this, 5 research axes are proposed:     

1- To identify cell determinants and signalling pathways involved in resistance in order to develop new biomarkers and dedicated targets 2- To evaluate new imaging tools for early diagnosis and follow-up after loco-regional treatments 3- To study response to loco-regional treatments in spontaneous and induced animal models 4- To develop diagnostic and therapeutic clinical approaches to decrease the tumour and host trend for resistance 5- To strengthen the access to care and reduce delays in the initiation of treatment, that may strongly influence host (and probably tumour) resistance

Moreover, two emerging programs will be developed (see Chap III.3.4):  

To improve efficiency in one of the loco-regional treatment, radiotherapy, with the development of a transversal Monte-Carlo dose engine To model the morbi-mortality of primary liver cancer in France across different stages of severity: evaluation of different strategies according to amount of screening and therapeutic resources.

These integrated axes will offer the possibility to reinforce the interaction between clinical, translational and basic research with a common goal of enhancing patients‟ survival, quality of life and quality of care. Results coming from basic and translational researches will be transferred to clinic, as much so as data generated across clinical trials will feed the fundamental and translational research programs.

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III.2.1.2. METHODOLOGICAL BACKGROUND In the context of excess-incidence and mortality in the Nord-Pas de Calais region and an incredibly high number of patients treated for these targeted cancers, clinical teams involved in the head & neck, oeso-gastric, primary liver, lung and mesothelioma cancers have developed numerous clinical research programs characterized by (i) a large active file of patients, (ii) a large number of funded therapeutic trials, (iii) a national and international visibility. This on site clinical research had as its objectives (i) to improve cancer treatment by offering a large panel of trials dedicated to innovative strategies, (ii) to allow patients‟ access to personalized treatment in order to decrease resistance to treatments and improve survival, (iii) to integrate translational research programs, (iv) to rapidly integrate results from translational research to the bedside and (v) to contribute to reducethe reduction of health inequalities. Whatever cancer is treated, all the above pathologies are characterized by a strong affinity with loco-regional treatment resistance. The vast majority of patients will have residual tumour tissue after chemotherapy, radiotherapy, chemoembolization, radiofrequency, immunotherapy or surgery, defining the tumour resistance and leading more and more to consider various associations between those treatment options. Despite empirical associations of treatments, knowledge of parameters that lead to predict before or during the therapeutic sequence the resistance to such loco-regional treatment is poor. Identification of common mechanisms sustaining chemoresistance in cancer as well as specific determinisms for each of these cancers are urgently needed. Moreover whereas many research programs are frequently oriented to identifying tumour factors linked to resistance, there is more and more evidence that the host plays an important role as well. However very little is still known (Pubmed : (Tumour resistance) AND (local treatment): 911 publications since 2006), about the underlying cellular and tumour mechanisms involved, the respective roles of the tumour and the host in such resistance, as well as the ways to anticipate and predict this phenomenon and the therapeutic tools necessary to fight against this fatal event. Even if, based on the knowledge of such high level of resistance in these cancers, many clinical trials on site have been empirically designed to define the optimal treatment strategy for each patient and each cancer (clinical research programs, coordinator C Mariette), various additional and complementary approaches have been initiated in order to improve the understanding of the determinants leading to tumour resistance: identification of the underlying cellular mechanisms and signalling pathways involved (basic research programs, coordinator Y De Launoit), identification of the biological and genetic predictors of resistance (biology and pathology platforms, coordinator N Porchet), modelling of spontaneous or inducible tumour resistance in animal models (animal facilities coordinator D Tierny), imaging modalities to detect early tumour resistance (coordinator I Fournier), conceptualizing appropriate study designs (clinical research platforms, coordinator A Duhamel), and determine human and social components that may impact on tumour resistance through suboptimal access to care and treatment initiation delays (coordinator V Christophe). The following opportunities are unique in strengthening the present program 

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A large local recruitment of head & neck, oeso-gastric, primary liver, lung and mesothelioma cancers: the Lille region recruits more patients into trials dealing with each of these cancers than any other region in France, and is one of the top 3 recruiting centres in Europe A unique potential in France to develop such an integrated research program due to the high specificity and visibility of the Lille region in upper GI, head and neck, mesothelioma and primary liver and lung cancer A dedicated research activity on these poorly studied cancers in which few academic groups or industrial companies are emerging. In fact, industrial partnerships usually prefer to sustain research programs issued from large specialized centres, due to well-known difficulties


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to drive programs in these cancers: patients with numerous co-morbidities, complex diagnostic and therapeutic strategies, lower recruitment rates... This may give a strong value to this program since (i) the probability for having another relevant integrated program on these pathologies in France is scarce, (ii) the SIRIC label will offer a unique opportunity to intensify research and partnerships dedicated to these cancers. An intensive clinical research activity based on a panel of more than 400 studies per year, including a large number of Phase I-II trials and dedicated regional or national cohort studies driven by the C2RC (examples of available cohorts > 2000 oesophageal cancers, > 3000 gastric cancers, > 1000 liver cancers… ) (See appendix; chapter 2). Already designed induced or spontaneous animal models dedicated to evaluate the impact of both tumour and host factors to cancer resistance Numerous funding from the National Cancer Institute (PAIR, PHRC, ICTs), ARC, National League against cancer, Regional Council, Fondation pour la Recherche Medicale Active industry-sponsored research trials (BMS, Novartis, Bayer Schering Pharma, Abbott, Pfizer, Roche, Merck, Nestlé, GSK, Amgen, Boehringer-Ingelheim, DAichi, CosBio, Transgene, Pierre Fabre) Integrated clinical research units dedicated to each cancer with a central coordination (CRC) Comprehensive, high-technology facilities (biology, serial and functional imaging, surgery, radiotherapy, medical oncology) and Human and Social Sciences departments Collaborative national and international groups involved (GORTEC, GETTEC, EORTC, PRODIGE, FFCD, FRENCH, FREGAT, IFCT, ELCWP etc.) Regional organizations for the management of primary liver cancer (networks: CIRRTRANS, interregional network CARNOR, S Dharancy), oesophageal cancer (OESO data base C Mariette), lung and mesothelioma cancers (CBNPC 59-62 database A Scheerperel) Socio-economic conditions in the region known as often unfavourable, combined with a relatively low medical density leading to intense recourse activity.

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III.2.1.3. ASSETS OF LILLE’S TEAMS Overview    

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Critical mass of researchers and A+/A research teams working in the field of resistance to loco-regional treatments: 10 teams; 30 researchers Availability of dedicated platforms with availability of serum and tumour banking with a hot topic on tumour resistance: 42 teams in methodology, imaging, fundameltal biology and HSS. Available large data bases dedicated to the targeted cancers Strong involvement of clinical researchers in programs investigating both tumour and host factors that may lead to tumour resistance: 13 clinical researchers, 79 dedicated clinical programs National and international research collaborations on these cancers based on a strong national leadership Important contributions to local scientific structuring and networks of collaboration partnerships linking Research in Oncology Already strong interactions between the actors of the program‟s axes as illustrated by numerous common publications and ongoing multidisciplinary funded programs (INCa PHRC,STIC, ARC; Ligue contre le Cancer ) High level of scientific production and international visibility: more than 800 publications in Oncology referenced in Medline since 2006 (cancer AND Lille[Affiliation]), more than 400 invited conferences, coordination of many national


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Partnership with regional or national scientific societies: FFCD, PRODIGE, UNICANCER, FRENCH, SFCD, SPLF, ERS, IASLC, IMIG …

Well established clinical and translational research 

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Strong valorisation and translation into clinical applications : in 2010, 80 clinical trials sponsored by the Lille University Hospital or the Cancer Centre, including 14 translational research trials and 18 PhaseI/II trials, with more than 1300 included patients, 440 studies sponsored by academics or industrial companies, with more than 1000 included patients (see appendices 2 and 5), partnerships with biotech (Lunginnov, CisBio International, ....) and the pharmaceutical industry (BMS, Novartis, Bayer Schering Pharma, Abbott, Pfizer, Roche, Merck, Nestlé, GSK, Amgen, Lilly, MSD, DAichi, Mundipharma, Eisai, IRIS/Servier, Fortis....) Long lasting collaboration between the COL, the CHRU and platforms. International recognition of clinician leading European networks in particular in oesogastric cancer (C Mariette), liver determinants leading to cancer resistance (P Mathurin, S Dharancy), tumour determinants of resistance in Head and neck (JL Lefebvre) and mesothelioma(A Scherpereel) cancers On going basic research and clinical trials aiming at reinforcing the host against the tumour (immunonutrition in oesogastric cancer (Nestlé), anti MAGE A3 immunotherapy against oesophageal tumour cells (GSK), pro-apoptotic drugs such as HDAC inhibitors in lung cancer (ELCWP 01081 trial) or malignant pleural mesothelioma (IRIS/Servier, ELCWP 01062 trial), immunostimulant to fight lung cancer (Talactoferrin – Fortis), Immune response to pleural malignancies assessment and induction (academic study), pharmacogenetic and pharmacodynamic evaluation of response to induction chemotherapy for head and neck cancers, anti EGFR targeted therapies (monoclonal antibodies: cetuximab, panitumumab, zalatumumab or anti-thyrosin kinase inhibitors: afatinib, lapatinib), prediction to cetuximab infusion-related reaction, place of integrin inhibitors (cilengitide) in recurrent/metastatic diseases, combination of cytotoxic drugs and molecular targeted therapies for larynx preservation… National reference centre for rare diseases such as malignant pleural mesothelioma, (Label by the French Ministry of Health and DHOS)

Access to multiple integrated platforms (see paragraph VI.3.1) Multiple national and scientific programs with financial supports (see appendix IV) Partnership with different pharmas on national and international clinical trials Sponsored by the COL, CHRU, French Intergroup of Thoracic Oncology (IFCT), European Lung Cancer Working Party (ELCWP), Nestle, Merck, GSK, Amgen, Boehringer-Ingelheim, Lilly, Roche, IRIS-Servier, Daichi, EISAI… Oesogastric location 

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National and international trials with Nestle (Switzerland and France) for developing immunomodulating nutritional supports with the aim of enhancing immune status to increase response to loco-regional treatment in both preclinical and clinical studies (C Mariette 2005 ongoing) Contracts/collaboration with Meck-Serono (Germany) to test immunotherapy to decrease resistance to loco-regional treatment in clinical studies (phases I and II trials) (PI C Mariette 2009 – ongoing, A Adenis 2007 under publication)


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Contracts/collaboration with GSK (USA) for basic, preclinical and clinical development of immune therapy in oesophageal cancer to enhance host anti-tumour activity (C Mariette 2011 - ongoing)

Pleural and lung cancers  

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International clinical trials to test news vaccines against lung cancer (targets: MAGE-A3 (GSK) or MUC-1(Transgene) (A Scherpereel 2009- ongoing) International collaborations to assess the value of histone deacetylase (HDAC) inhibitors to overcome tumour cells resistance to apoptosis, alone or in combination with chemotherapy, in pre-clinical models and in clinical trials for malignant pleural mesothelioma or small cell lung cancer (PI A Scherpereel): MSD trial (vorinostat – closed), ELCWP 01062 trial (valproic acid – closed, publication Eur Respir J 2011), IRIS/Servier (S78454: 2010 - ongoing), ELCWP 01081 trial (valproic acid: 2010 - ongoing) International collaborations to assess the value of non reversible EGFR TKI (A Cortot – 1 publication) or anti-MET therapies to overcome tumour cells resistance to anti-EGFR TKI in non small cell lung cancer (NSCLC): pre-clinical models (D Tulasne and A Cortot) and clinical trial (A Scherpereel – ARQ197 from Daichi)

Primary liver cancer 

International clinical trials testing multimodal therapy and targeted therapies directed against primary liver cancer in collaboration with BAYER, NOVARTIS, ABBOTT, PFIZER and BMS. - 3 Phase II trials: SEARCH : Sorafenib and Erlotinib, a RAndomised TRial ProtoCol for the treatment of patients with Hepatocellular carcinoma; SPACE: A Phase II Randomized, Double-Blind, Placebo- Controlled Study of Sorafenib or Placebo in Combination with Transarterial Chemoembolisation (TACE) Performed with Drug-Eluting Beads and Doxorubicin for Intermediate Stage Hepatocellular Carcinoma); LIGHT: Sorafenib and Erlotinib, a RAndomised TRial ProtoCol for the treatment of patients with Hepatocellular carcinoma. - 6 phase III trials: BRISK FL (first line brivanib vs sorafenib); BRISK PS (second line brivanib vs placebo); BRISK TA (brivanib vs placebo after TACE); STORM (Randomized, double-blind, placebo-controlled study of Sorafenid as adjuvant treatment for hepatocellular carcinoma after surgical resection or local ablation); SUN (first line sorafenib vs sunitinib); EVOLVE (second line everolimus vs placebo). - 1 phase IV trial: GIDEON (Nexavar Non - Interventional Study in HCC)

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National clinical trial on the behalf of PRODIGE-FFCD group: SATURN (sunitinib vs placebo after DC BEADS TACE) Collaboration with a veterinary platform (ONCOVET and OCR), working with canine models of spontaneous liver tumours (see chap III.3.2.1) in Pre-human phase 1 studies.

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Head and neck 

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International collaboration on prevalence of HPV-associated or pharyngeal cancer (Centre Oscar Lambret as the French representative for the International survey coordinated by Maura Gillison, MD, John Hopkins Hospital) International collaboration (US, EORTC, GORTEC) on larynx preservation guidelines and clinical research (JL lefebvre, Centre Oscar Lambret) Collaboration with Merck-Serono, Boerhinger-Ingelheim, Amgen, Genmab for clinical evaluation of anti-EGFR in jlocally advanced or in recurrent/metastatic head and neck cancers.


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National (INCa) contract for morphologic and molecular evaluation of head and neck cancer in patients without known risk factors National contract for evaluation of salivary test for early detection of head and neck cancer Collaboration with a veterinary platform (ONCOVET and OCR), working with feline and canine models of spontaneous head and neck tumours (see chap III.3.2.1) in Pre-human phase 1 studies.

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III.2.1.4. TEAMS, INSTITUTIONS AND INFRASTRUCTURES INVOLVED IN PROGRAM 1 

Research Laboratories : Laboratory of Cell Division Signaling EA 4479 lille1, CNRS UMR8161, Interdisciplinary research group, therapeutic EA 4481 lille2, INSERM U837 , CNRS UMR 8576, EA 4550, Lille1

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Translational Research Pole : Centre de Biology pathologyBP, Genetic platform, tumor bank

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Clinical Research Departments: Methodology and biostatistic unit, Clinical research unit and Methodology and biostatictic unit of the COL and EA 2694 (health economy) and the Clinical research unit of the CHRU.

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Clinical Medical Departments COL: Head and neck cancer department, Urology and digestive oncology department and CHRU:Medical oncology department, Department of digestive and oncological surgery, Gastroenterology and hepathology department, General and Digestive surgery, Pneumology and chest oncology CHRU,

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Human and Social Sciences Departments: Registre des cancers de Lille et de sa région, EQUIPPE EA 4018, EQUIPPE EA 4018, GERiiCO - EA4073 of lille3)

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III.2.2. MAIN TARGETS OF THE PROGRAM’S WORK III.2.2.1. BASIC RESEARCH Task 1: Identification of molecular and cell mechanisms linked to resistance to treatments Participants 

JF Bodart, Y de Launoit, D Chevalier, P Delannoy, JF Goossens, A Lansiaux, T Lefebvre, O Melnyk, JC Michalski, A Scherpereel, F Soncin, D Tulasne, I Van Seuningen

Targeted therapies interfere with specific targets needed for tumour growth, rather than interfering with rapidly dividing cells like traditional chemotherapy. The tyrosine kinase receptors (RTK) are well-known targets since they are often deregulated in cancers. The EGFR is one of these targets, with monoclonal antibodies or ATP-mimetics used in therapeutic treatments in lung, colon and head and neck cancers, displaying mutations or over-expression of the receptor. These treatments increase significantly the survival of the responding patients. However, non-responding or resistant patients, established during treatment, induce many therapeutic failures. The resistances involve additional mutations of the EGFR receptor itself. However, resistance also involves 1-overexpression of other RTKs (like the Met receptor), which bypass the activation of the downstream signalling pathways and 2-alteration of RTKs activity because of their interaction with different membrane partners. Thus, the identification of molecular mechanisms from the membrane receptors to the integration of the signalling involved in these resistances is an important issue to improve the therapeutic efficiency. Several teams in Lille are investigating the involvement of RTK and their membrane partners in cancers of epithelial origin. They will contribute to this task by developing new models (in vitro and in vivo) adapted to the cancers studied in the ONCOLILLE consortium to better understand molecular mechanisms associated with resistance to loco-regional treatments. 1. Identification of molecular mechanisms from membrane receptors to biological effects Many patients with lung or colon cancer develop resistance to anti-EGFR therapies induced notably by amplification of the MET receptor. The researchers of the “Institut de Biologie de Lille” (IBL) conduct research on MET (the HGF/SF receptor) to understand the molecular mechanisms leading to tumourigenesis and to characterize new anti-MET molecules interacting specifically with its extracellular domain (Foveau et al., 2009 – Ancot et al., 2009). Recently, the team of O Melnyk developed a new chemical method to synthesize, by native chemical ligation and bis(2sulfanylethyl)amido ligation, part of the MET ligand, i.e. the K1 domain of HGF/SF which has been proved to be biologically active (Ollivier et al., in press). This approach developed at the IBL opens new avenues to design active MET antagonists and will be extended here for the other tyrosine kinase receptors studied. At the University of Lille 1, the team of Xuefen Le Bourhis also studies signalling initiated by other RTKs, especially TrkA (receptor of NGF), and has notably shown the implication of NGF/TrkA axis in breast cancer development using preclinical animal models (Adriaenssens et al., 2008 - Lagadec et al., 2009 – Le Bourhis et al., 2010); functional proteomics approaches being now developed to identify downstream signalling pathways. A translational research program involving the IBL, the CHRU, the COL and the University of Lille 2 (A Scherpereel, D Tulasne, V Fafeur, A Lansiaux and JF Goossens) is currently being conducted to both identify and functionally characterize specific MET (and TRK) receptor mutations in antiEGFR-resistant tumours. This already led to the characterization of the cytotoxic/resistance

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activity of drugs (Gluszok et al., 2010) and the discovery of an original mechanism of EGFR resistance in head and neck cancers (Rebucci et al., 2011). Deregulation of other signalling pathways downstream from the RTK is also involved in anti-EGFRresistant tumours (Olivier et al., 2011). Recent data were obtained by the group of Tony Lefebvre (University of Lille 1) on mammary and colorectal cancers cells (Olivier et al., in press) on the Wnt/beta-catenin pathway regulated by post-translational modifications (such as OGlcNAcylation). On the other hand, the interplay between ganglioside and MET was also demonstrated since P Delannoy‟s team (University of Lille 1) has recently shown that G(D3) synthase expression is sufficient to enhance the tumorigenicity of breast cancer cells through a ganglioside-dependent activation of MET (Cazet et al., 2010). Finally, an integrative approach to decipher the complexity of the MAPK network (Bodart, 2010), which is triggered by RTK in cancer is developed by the group of JF Bodart (University of Lille 1) and exhibits a specific dynamic signature (Gao & Zhang, 2010). We propose here to investigate the role of RTK deregulation in these three above-mentioned preventable cancers, paying special attention to MET, TRK and Wnt/beta-catenin pathways. We will also focus on the interplay between ganglioside and MET and we will develop an integrative approach to decipher the complexity of the signalling network. The aim of this part of the program is thus to characterize new biomarkers for orienting current treatments and to anticipate future targeted therapies against RTK or downstream signalling with the aim of decreasing tumour resistance to treatments. In parallel with these translational approaches, the functional consequences of RTK signalling deregulation will be investigated in cellular models to evaluate notably the consequences of mutations in cell transformation or the influence of extracellular modifications associated with the tumour micro-environment, such as acidification under hypoxic conditions, on cell survival and chemoresistance (J Vicogne and A Lansiaux), as well as the recently identified role of EGFR as a virus entry cofactor in HCV-induced hepatocarcinoma (group of N Delhem at IBL). We will exploit these established models to study the potential role of such phenomena in the targeted cancers. In a preliminary step, we will examine expression levels and/or the mutation status of the studied markers. Functional studies will then be performed to exploit the knowledge gained by these teams in newly established cell models: oral, oeso-gastric (already available in the team of I Van Seuningen) and mesothelioma cancer cells. 2. Role of the membrane partners of RTKs in resistance to loco-regional treatments (chemoresistance) In close relationship with programs from §1, several laboratories in Lille have developed research on oncogenic receptor membrane partners (mucins, gangliosides…) to evaluate their implication in resistance of tumour cells to loco-regional treatments. At the JPARC research Centre (University of Lille 2, the team of Isabelle Van Seuningen (Inserm UMR837, team 5) has shown that the MUC1 and MUC4 mucins are overexpressed in various cancers of epithelial origin, including oral and oeso-gastric cancers, participate in chemo sensitivity of tumour cells and are direct actors in tumour progression, as they are membrane partners of EGFR (MUC1) and ErbB2 (MUC4) (Jonckheere & Van Seuningen, 2008 - 2010). Mucins are thus phenotypic markers of tumour differentiation (mucinous versus non mucinous), prognostic markers (over-expression and altered localisation of membrane mucins are often associated with tumour poor prognosis and/or with tumour drug resistance), and diagnostic markers (MUC1 detection in numerous epithelial cancers). For many years, members of this team (I Van Seuningen, P Pigny, G Huet, M Perrais) have developed strong translational research with several clinical departments of the Lille CHRU (MC Copin (CBP, tissue expression), Nicole Porchet (CBP, mutations/polymorphism/methylation), JP Triboulet/C Mariette (digestive surgery, oesogastric cancers), FR Pruvot (digestive surgery, colon and pancreatic cancers), and A Villers (renal

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cancer). Moreover, mouse and rat preclinical models of epithelial carcinogenesis have been developed by this team or are available thanks to strong international collaborations. Finally, spontaneous models of naturally occurring epithelial tumours (head and neck and hepatic tumours) will be available (OCR, Oncovet) to secure the preclinical to clinical transition of diagnostic, prognostic and more important therapeutic candidates. Alongside the research on oeso-gastric cancers already developed in this team by Christophe Mariette (Piessen et al., 2009), it is now proposed to initiate parallel research projects on the role of mucins in the other cancers studied in ONCOLille consortium (head and neck, liver). Continuing the strong collaborations with the pathology department of the Lille CHRU (MC Copin), we now propose to investigate, retrospectively and prospectively, expression levels of membrane-bound mucins in tumour tissues for a correlation to loco-regional treatment resistance. The studies proposed in this project (biomarker identification, structure-function relationships) will benefit from the knowledge and expertise gained from the rat model of refluxinduced oesophageal cancer, developed in the team (FRM-label team). The ongoing establishment of the same model in mice will be very useful in order to study the role of reflux in genetically modified mouse models either obtained in collaboration or developed in the laboratory. More recently, this team (MP Buisine) has found a correlation between mucin gene methylation and tumour differentiation (MSI/MSS colorectal cancer). Detection of mucin gene methylation in epithelial cancers is thus a promising (prognostic, predictive) tool for clinical anticipation of tumour resistance, and will be tested in the cancers studied in the ONCOLille consortium (Van Seuningen & Vincent, 2009). Based on the experience gained by this team that established numerous chemoresistant cellular models (colon, pancreas, kidney) (Jonckheere et al., 2009; Aubert et al., 2009; Dessein et al., 2010; Merlin et al., 2011), new models will be developed to study the role of RTKs membrane partners in oeso-gastric, lung and liver cancers and their resistance to chemotherapeutic drugs. These cellular models will be also very useful for studies developed by research teams in §1 of this task. 3. Angiogenesis, tumour endothelium and escape from immunity Tumour blood vessels are essential for the growth of most solid tumours and for metastasis. The tumour blood vessel endothelium, although imperfectly tight, actively protects tumour cells from the immune system through its barrier function. Tumour escape from immunity can be achieved by preventing the infiltration of effector immune cells through the down-regulation of endothelial adhesion molecules. F Soncin‟s team (IBL) has originally characterized Egfl7 (VE-statin) as specifically expressed by blood vessel endothelial cells in normal organs during development and in the adult and shown that Egfl7 alters blood vessel elastogenesis (Soncin et al. 2003 Lelièvre et al. 2008). This team has recently shown that Egfl7 promotes tumour growth and metastasis by protecting tumours from the host immune response through the down-regulation of leukocyte adhesion molecules by tumour endothelial cells (Delfortrie et al. Cancer Res, in press). In human cancer, expression levels of egfl7 is deregulated and correlates with a higher tumour grade in glioma and in colon cancer patients, and with a poorer prognosis and higher metastatic score in hepatocarcinoma patients. The current projects are aimed at understanding the role of Egfl7 and its partners in the development of tumours and at assessing the correlations between angiogenesis, egfl7 expression, immune status and prognosis in patients having the different cancers studied in this project. The benefit of spontaneous large animal tumour models (which could be provided through collaboration with OCR and Oncovet) over mouse models in this topic is evident, as the study of neo-angiogenesis is simplified by the large size of tumours, allowing vascular tissue isolation. Through collaboration between the Biology platform and OCR, we could validate a highly predictable preclinical model for study of anti-angiogenic drugs toxicity and efficiency.

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Pathologies Head and neck, oeso-gastric, primary liver, lung and mesothelioma cancer Deliverables   

(M12) Validation of the signaling pathways in targeted cancers (M24) Validation of the identification of molecular mechanisms associated to RTK and Mucin activity in the targeted cancers (M 36) Develop animal models (murine xenografted...) for the study of resistance to treatment or angiogenesis in targeted cancers.

Task 2: Animal models to determine physio-pathological processes linked to primary or secondary tumour resistance Participants 

IMPRT (D Taillieu et T Hubert), Tumour model platform (IBL), IFR 114, Oncovet Clinical research (D Tierny), U837 (I Van Seuningen, C Mariette)

Objectives To identify physio-pathological processes leading to chemoresistance and peritoneal dissemination in gastric signet ring cell carcinomas (C Mariette): Having shown in a local and national cohort studies (Piessen Ann Surg 2009, Messager Ann Surg 2011, Mariette JCO 2012 in press) that gastric adenocarcinoma, especially signet ring cell histology when compared to well-differentiated adenocarcinoma, are characterized by (i) a poor prognosis, (ii) a high lymph node and peritoneal affinity and (iii) a high degree of chemoresistance, in addition to clinical trials funded to identify an optimal therapeutic strategies (Inca PHRC grant phase II/III trials 2011), cellular models and a dedicated mouse model have been created to identify the physiopathologic endpoints explaining tumour characteristics and chemoresistance To understand the carcinogenetic sequence mechanisms from metaplasia to adenocarcinoma in an oesophageal rat model ubmitted to biliary and acidic reflux, in order to identify key factors leading to cancer and sustaining chemoresistance (numerous grants from Ligue contre le Cancer, and team labellisation from the Fondation pour la Recherche Medicale Pi C Mariette) To assess presence of diagnostic and therapeutic targets, and response of tumour to treatment in canine models of spontaneous head and neck and liver tumours (Collaboration with a veterinary platform ONCOVET and OCR). Already used dog models represent a reliable model of naturally occurring head and neck and liver tumours, and these share many similarities with human tumours. Similar diagnostic and follow-up imaging procedures and treatments could be proposed in these species, and serial biopsies of the tumour could be obtained. They share also a natural history, epidemiological and environmental factors and response to treatments with their human counterpart. “Pre-human phase 1 studies”, providing information on safety and efficacy of both diagnostic and therapeutic modalities can be consequently reliably be carried out. To propose and validate a preclinical model of oeso-gastric spontaneously resistant tumours in dogs,

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Ffactors explaining tumour characteristics and chemoresistance identified in mouse models will be validated. Additionally, study tumour dormancy phenomenon, in interaction with program 2, will be extensively studied in a model of canine mammary carcinoma and non-Hodgkin lymphoma, a model in which tumour dormancy with systematic and (relatively) rapid relapse is observed in most case within one year after initial treatment-induced remission. Pathologies Oeso-gastric cancers, liver and head and neck cancers. Deliverables 

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(M12) identification in canine models of key factors (tumoral and host-related) leading to tumour resistance. Dogs will be treated with previously published protocols of surgery, radiation therapy and/or chemotherapy. Previously published and newly identified negative prognostic factors will be used for further stratification of canine patient. (M 12) Identifying molecular markers from available induced and spontaneous animal models (M24) Specifically designed therapeutic strategy will be proposed in prospective clinical trials using : - previously identified prognostic markers for tumoral and host-related résistance ; - previously published data regarding efficiency and toxicity of conventional radiation therapy and chemotherapy in dogs with spontaneous tumours ; (M 24) Identifying new molecular markers from induced and spontaneous animal models (M 24) Identify molecular mechanisms responsible for chemoresistance (M48) Identify molecular mechanisms responsible for chemoresistance in targeted cancers (M 24) Drug testing on animal models (M 36) Publication or patent: Animal models for other locations (M 48 - 60) Develop clinical trials in humans

These studies will allow identification of tumour response to multimodal therapeutic strategy through serial tissue sampling.

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III.2.2.2. TRANSLATIONAL RESEARCH Task 1: Genetic, biological and pathologic factors linked to host and tumour resistance Participants 

N Porchet, Copin MC, A Scherpereel, S Dharancy, C Mariette, JL Lefebvre, D Tierny

Objectives To identify tissue and molecular makers linked to response to loco-regional treatment and prognosis Based on the dedicated platforms (see paragraph VI.3), the aim is to develop and validate new tissue and molecular markers characterized by a specific mutation or proteic expression or a genic amplification. This will allow proposing a dedicated and innovative treatment for a tailored therapeutic approach, taking into account both host and tumour factors linked to resistance to loco-regional treatments. This translational research is based on a strong collaboration between basic science researchers, pathologists, geneticians, surgical and medical oncologists, as well as veterinary research and imaging research departments with a common objective that is to identify mechanisms involved in tumour progression and resistance Examples of some ongoing research programs are listed below: 

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Identification of emerging biomarkers that will escort the development of targeted therapies in lung and mesothelioma carcinomas, already tested in phase I/II, III, clinical trials, such as reversible inhibitors of EGFR and HER2, MET/ALK, MEK, mTOR, PI3K/mTOR inhibitors Determining the role of TLR4/P2RX7 in oesophageal cancer chemo radiation resistance (collaboration with the A+ research unit Inserm U848 Apoptosis, Cancer and Immunity L Zitvogel Paris) and the Lille surgical department of surgery (C Mariette) (Apetoh et al. Immunol review 2007) Definition of signalling pathways involved in response to immune therapy by cetuximab in oesogastric cancer (PI C Mariette, Merck-Serono sponsorized grant 2010) Identification of mechanisms involved in the immune host stimulation through immunonutrition administered during chemo(radiation) and surgery in oeso-gastric cancers (PI C Mariette, Nestlé sponsorized grant 2010 Methylation pattern of the mucin genes: predictive factors of tumoral resistance (collaboration with Inserm U837-Team 5) (Vincent A and Van Seuningen I, Expert Opin Med Diagn 2009) Understanding recurrence through mechanisms of metastasis (link with program 2): Having shown that chemotherapeutic agents led to the emergence of residual chemoresistant cancer cells that highly expressed the chemokine receptor CXCR4 and that this receptor played a crucial role in invasion of collagen matrix and metastatic dissemination in marine xenograft models(Dessein et al Cancer Res 2010), this model can lead to identify common mechanisms linked to resistance to chemotherapy agents among targeted cancers.

Pathologies Oeso-gastric cancer, lung cancer and malignant mesothelioma, head and neck cancer Deliverables   

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(M12) emerging biomarkers for targeted therapies (M12) Methylation of mucin genes as predictive markers (M36) murine xenograft models


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Task 2: Imaging techniques for early identification of tumour resistance Participants 

I. Fournier, D. Huglo, M. Salzet, D. Tierny, E. Lartigau

Objectives In vivo cancer imaging technology needs specific targets. It implies simultaneously tumour localisation and following the tumour biology. This needs to increase multimodal imaging like PET and Computer Tomography (CT) or PET/MRI. Traditional clinical measures of relapse include disease progression, usually defined as a 20% or greater increase in tumour size, appearance of new lesions, or death. SPI offer a large imaging platform with various imaging modalities relying on a large number of various instrumentations offering the opportunity for high level translational research to be applied for cancer relapse and resistance to treatments. In SPI, multimodal imaging will also associate in vivo imaging to ex vivo molecular imaging (MSI) for a better diagnosis by combining MRI, PET-SCAN, CT-SCAN technologies to mass spectrometry imaging and biophotonic in order to give molecular information through new proteins or specific miRNA detection. This allows covering from very fundamental research on resistance of host and tumour for better understanding of biological mechanisms involved and for defining new key molecules of these signalling pathways up to translation better diagnosis and prognosis of resistance or for looking to new therapeutic targets and treatments. Fundamental research will start from cellular models to be translated to animal models up to patient outcome thus allowing to improve the uptake of patients according to inter individual variability for more personalized medicine. 1. To image known molecules in cancer resistance from basic and clinical research. The aim of this first objective is to better understand the role of these particular molecules in the resistance and to define the underlining mechanisms through increased knowledge on signalling pathways. This objective is highly integrative since it will cover basic research on cellular models up to functional imaging in medium size animals with spontaneous tumours which are closer to human pathologies. This will be undertaken under several angles and at decreasing scale range (mm down to nm scale) using the various imaging modalities available at the ONCOLille SPI Platform. In this context, due to the fact that cell signalling pathways play a central role in cancer cell growth, survival, invasion and metastasis and the fact that discovering the "circuit maps" of these signalling pathways seems a high challenge for detecting novel therapeutic strategies, a large effort will be concentrated to image both specific inhibitors of such pathways (drugs, miRNA, cytotoxic antibodies), localize into the tumours the efficiency of such therapeutic tools and the impact though functional and molecular imaging of these treatments on the tumour. In this context, anti-MET molecules developed by the ONCOLille teams will be tracked by ONCOLille SPI Platform using multimodal image technologies in order to get a complete integrative response from functional to molecular images and from global to intracellular response. For this, models animals will be firstly used and anti-MET (drugs, therapeutic antibodies will be labelled with radioisotopes such as 64Cu) for PET-Scan analysis in conjunction with MRI images in order to follow the inhibitor in vivo. Resected tumour will be then analyzed in whole body mass spectrometry imaging (MSI) in order to localize and quantify the deep access of the inhibitor into the tumour and its impact in the tumour proteome. Biophotonic imaging will give the sub cellular information about the localization of the inhibitor into cell tumour for the understanding the mechanism of action of the inhibitor for evaluating the resistance that will occur during the treatment. Similarly, in order to better understand the interaction between gangliosides and MET, labelled anti-Gangliosides will be developed, used on animal models and will be trace by PETSCAN/MRI. Again, resected tumour will analyzed by MSI and the interaction between the lipid

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and the MET will be analyzed at a molecular level by giving the spatio-temporal localization of the interaction and the partners present in the same localization. Resistance to anti-EGFR will be also undertaken by focusing on Wnt/beta catenin pathway through targeting MAP kinase pathway partners by labelling each of them and image them by PET/MRI. Moreover, fundamental studies on tumour resistance have shown the role of mucins like MUC1 and MUC4 in various cancer including oral and oeso-gastric cancers. These Mucins have proteins partners EGFR and ErB2. It is thus important to understand such interaction in course of tumour developments and find the specific partners implicated due to their interaction. Animals models developed at ONCOLille or ONCOVET will be used. Specific antibody tracers for MUC1 and MUC4, PET tracers will be developed and used for in vivo immuno- PET-SCAN imaging. Immuno-PET is a quantitative imaging procedure before or concomitant with radioimmunotherapy. Radioimmunotherapy (RIT), consisting of radionuclides coupled to monoclonal antibodies (mAbs) like 90Y-ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals) and 131I-tositumomab (Bexxar; Corixa Corp.) will be used for this project. Coupling PET-SCAN to MSI will allow getting antibody distribution in the animals in course of the pathology development and their penetration into the tumour. MSI will also bring the opportunity to see the impact at the lipidome and proteome level of such treatments. In the same way, the anti-angiogenic drugs, the EGFR and HER2, MET/ALK, MEK mTOR, P13K/mTOR inhibitors will be followed in the whole body animal by PET/MRI and their distributions, quantification in tumour by qMSI developed by IMABIOTECH SAS. Considering the teams working on the Interaction between TLR4/P2X7 or CXCR4, such fundamental work will be undertaken firstly by biophotonic imaging for understanding the cellular and molecular mechanisms occurring during their interaction using of OxATP and brilliant blue G antagonists of P2X7I. But also, by the development of [18F]-ML-10 as PET radiotracer, this will give access to in vivo imaging for such receptor and its partners. Thus it is now clear that all markers, inhibitors, drugs, antibodies developed by ONCOLille Teams will be directly analyzed and imaged by SPI. This is a complete close interaction between fundamental researches to translational research through the development of specific imaging technologies in close interaction. 2. To search for new key players of cancer resistance mechanisms in order to define new early diagnosis and prognosis markers. This objective can be achieved at different level using different imaging modalities. MALDI Mass Spectrometry Imaging has demonstrated high potential for highlighting molecular contents regulation demonstrating change of cell phenotypes up to identification of these molecules through structural elucidation strategies for many endogenous compounds such as metabolites, lipids, peptides and proteins. MALDI MSI group of ONCOLille has previously demonstrated the identification of new potential markers of ovarian cancer in prospective or retrospective studies using archived hospital bank samples. Similar methods will be applied to find new compounds that could be use for early diagnosis of cancer resistance. The found markers will be crossvalidated using histology and IHC through the pathology platform of C2RC. 3. To study the impact of new treatments or new drugs. Based on fundamental knowledge from the basic and clinical research new treatments combining several already known treatments such as known drugs with radiotherapy will be assayed on animal models in particular medium size animal models with spontaneous tumours. New potential therapeutic targets discovered through the collaborative work between teams will be used for the development of new drugs such as therapeutic antibodies. Drug distribution will be studied using the various imaging modalities. In vivo imaging will allow performing fine kinetic studies of drugs distribution. MSI will be used to obtain drug distribution at the scale of a

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few cells in sections of organs or in whole body sections for rodent models. MSI will also bring knowledge on the possible identification of metabolites and their localization as well as highlight changes of the molecular content in the region targeted by the drugs. Biophotonic will be used for subcellular localization of the drugs giving better understanding on the drug‟s action mechanism of action. Combined PET/CT modalities is of added value here since it will allow to define from animal models, the response to treatment in patients after e.g. chemotherapy of radiation therapy though FDG uptake in cancerous tissues. 4. To use the acquired knowledge to define new functional imaging protocols for patients. This objective is aimed at achieving diagnosis and prognosis of cancer resistance by in vivo imaging screening and therefore determining the better treatment protocol to follow in order to prevent resistance to this treatment using new treatments or drugs in a more personalized approach. Here we particularly aim in promoting in vivo imaging for diagnosis trying to limit biopsy uptake from patients because of the need of surgery and because of possible side effects of regular biopsies on the development of carcinoma. 5. To develop new cutting-edge methodologies to improve the application abilities of the SPI platform. New methodologies using imaging modalities will help to gain new knowledge on cancer resistance. Combined PET/MRI imaging that is to be obtained through the SMART project will be used to improve imaging by giving access to more information. Such an instrument will help to resolve difficulties in studying the kinetics of drug distribution or for the validation of new therapeutics and markers which is difficult to achieve using separate imaging systems. Possible in vivo monitoring through Mass Spectrometry is also another challenge to screen early diagnotic markers of resistance with minimal intrusion for the patients. Development of in vivo MS screening is the opportunity to combine diagnosis and prognosis to fast treatment using new therapies such as PhotoDynamic Therapies to destroy cells (in particularly resistant cells) through laser irradiation. Development of new strategies of MSI is also an opportunity to increase knowledge with special attention paid to developing MSI imaging of miRNA. In fact, specific miRNA act as markers of pathologies. Pathologies Oeso-gastric cancer, lung cancer and malignant mesothelioma, head and neck cancer Deliverables      

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(M24) Integrated multimodal imaging platform (M24) Protocol for multimodal imaging of molecules known as potential target of cancer resistance (M36) Compendium of early diagnosis markers of cancer resistance (M36) Protocol for multimodal imaging of new drugs of cancer resistance (M48) New imaging methodologies (M60) Protocol for in vivo imaging early diagnosis of patients towards cancer resistance


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III.2.2.3. CLINICAL RESEARCH Task 1: Identification of clinical tumour and host determinants leading to resistance to loco-regional treatments Participants 

C Mariette, E Lartigau, JL Lefebvre, P Mathurin, A Scherpereel, M Hebbar, A Adenis, , A Lansiaux, S Dharancy, H Porte, FR Pruvot, G Piessen, A Cortot

Based on one of the highest incidence of head and neck, oeso-gastric, primary liver, lung and mesothelioma cancer incidence in France and worldwide, the C2RC receives a considerable volume of patients for diagnosis and treatment, 400 oesophageal cancers, > 1000 head and neck cancers, 450 hepatocarcinomas, 450 lung cancers and 50 malignant pleural mesotheliomas per year. This leads to an intensive clinical research activity organized around 4 major objectives described below. Objectives 1. To identify clinical determinants and predictive factors linked to chemo(radio)resistance: To date complementary clinical approaches have been used to identify patient subgroups most likely to benefit from specific treatments used in head and neck, oeso-gastric, primary liver, lung and mesothelioma cancers. Some examples are listed below        

Morphological and molecular characterization of head and neck tumours non related to tobacco or alcoholic consumption (PI JL Lefebvre, INCa PHRC grant 2007) Predictive factors of response to chemoradiation in oesophageal cancer (PI A Adenis, Regional Council grant) Stereotaxic irradiation of primary liver cancer using Cyberknife technology (PI X Mirabel, INCa PHRC grant 2008) Stereotaxic re-irradiation of Head and Neck cancer using Cyberknife technology (PI E Lartigau, Industrial sponsoring 2009) Clinical factors linked to chemoresistance in oeso-gastric cancer (PI C Mariette, Fondation pour la Recherche Medical grant 2007) Role of chemotherapy in patients with metastatic oesophageal carcinoma (PI A Adenis, INCa PHRC grant 2010) Molecular and clinical factors linked to acquired resistance to EGFR TKI in NSCLC, (PI A Scherpereel and A Cortot, industrial sponsoring Astra-Zeneca: 2010-) Biomarkers to predict resistance to treatments in malignant pleural mesothelioma (PI: A Scherpereel, industrial sponsoring Fujirebio and CisBio International: 2007-)

2. To develop diagnostic strategies for early evaluation of tumour resistance in order to switch early towards an appropriate treatment: One of the cornerstones for an early evaluation of the resistance to loco regional treatment is imaging based diagnosis. Many trials have been funded on our site whose primary objective is evaluate the role of metabolic imaging for a therapeutic image-guided approach, such as:  

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Role of the PET in the biologic targeting for conformational or modulating intensity radiotherapy in head and neck cancers (PI E Lartigau, INCa PHRC grant 2006) Role of PET in predictive response to neoadjuvant chemoradiation in oesophageal cancer ( PI C Mariette, INCa PHRC grant 2002, Ann Surg In press)


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New Imaging procedure (MDCT, PET-CT) and Biomarkers to predict the resistance to antiangiogenic drugs in lung cancer and malignant pleural mesothelioma PI: A Scherpereel and M Rémy-Jardin, industrial sponsoring Roche: 2010-; Amgen: 2011-)

3. To develop therapeutic strategies to decrease the tumour potential for resistance: Combination of treatments is the major way employed to fight against tumour resistance, associating frequently chemotherapy, radiotherapy and surgery. However, the optimal sequence of combination deserves further research in the ONCOLille consortium targeted cancers. Moreover since the introduction of immunotherapy treatment, such as cetuximab or bevacizumab, the impact of these therapies is under intensive research for colon and rectal cancers but with a lower interest for cancers targeted in this program. That is the main reason why many researchers involved in the present program have designed ongoing national or international trials dedicated to define optimal sequences and combinations of these treatments in head and neck, oeso-gastric, primary liver, lung and mesothelioma carcinomas, such as:   

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phase III trial testing the impact of chemoradiation in stage I and II resectable oesophageal cancers PI C Mariette, INCa PHRC grant 2002 J Clin Oncol in press, phase II-III trial testing the role of primary surgery vs. primary chemotherapy in resectable signet ring cell gastric adenocarcinoma PI C Mariette, INCa PHRC grant 2011 Phase I-II trial testing the impact of an immunotherapy (cetuximab) used in combination with chemotherapy and radiotherapy to decrease tumour resistance to standard chemoradiation regimen. PI A Adenis, Merck Serono industrial grant 2008 Role of mini-invasive surgery in oesophageal cancer Phase III trial PI C Mariette, INCa PHRC grant 2008 Role of surgery in patients with complete morphological response to neoadjuvant chemoradiation in oesophageal cancer PI L Bedenne - C Mariette, INCa PHRC grant 2012 (submitted) Phase II trials (2 academic trials, 2 supported by MSD and by IRIS/Servier) testing the value of pro-apoptotic drugs (HDAC inhibitors) to decrease the resistance to standard chemotherapy in malignant pleural mesothelioma or in small cell lung cancer (PI: A Scherpereel and T Berghmans). First results published in Eur Respir J 2011. Role of photodynamic therapy combined with pleurectomy/decortication and chemotherapy in the multimodal treatment of malignant pleural mesothelioma. PI: A Scherpereel, INCa PHRC grant 2012 (submitted) Kinetic assessment of tumour resistance in EGFR-mutated patients with NSCLC treated by EGFR TKI. PI: A Cortot, INCa PHRC grant 2012 (submitted)

4. To develop therapeutic strategies to decrease the host potential resistance. Based on the hypothesis that the host and the immune modulation may have a strong impact on response to loco-regional treatment, various clinical approaches have been used on site, such as: 

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Stimulation of the immune system through immunonutrition. Important results have been obtained in the peri-operative setting in numerous randomized trials. The unique and original approach developed in oeso-gastric cancer is to reinforce the host immune system during the whole therapeutic sequence from the beginning of chemotherapy to the postoperative care. An international trial to confirm this hypothesis is ongoing (PI C Mariette, Industrial European Nestle grant 2011). Targeting tumour cells via patients‟ immune system stimulation. Via a Lille partnership with the US GSK pharma, a specific target will be tested in oesophageal cancers (MAGE A3) to develop a dedicated vaccine therapy through preclinical, phases I, II and III trials (PI C Mariette, GSK grant 2011) – also a phase II trial in resected NSCLC (PI: A Scherpereel)


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Evaluating the optimal delay for hepatic transplantation after acute host assault: results from a national survey (Mathurin P, Dharancy S et al, New Engl J Med 2011).

Pathologies Head and neck, oesophageal, gastric, primary liver, lung carcinomas and malignant pleural mesothelioma Deliverables      

M6-M24 : Identification of clinical predictors for resistance from existing data-bases and numerous ongoing trials M6-M24: Identification of biological and cellular predictors for resistance M6-M48: Animal modelisation for resistance M36-M48: Design clinical trials testing therapeutic strategies based on host/tumour predictors for resistance identified M6-M60: Integration of data coming from research to the bed side M0-M60: Diffusion of the knowledge through publications, national and international communications and local networks

Task 2: To tailor clinical trials with the aim to identify factors linked to resistance Participants 

Clinical research Unit of the COL and Clinical Investigation Centre-Inserm (P Devos, A Kramar, A Duhamel, S Clisant, N Penel)

Objectives 1. To design clinical trials dedicated to subgroups of patients, characterized by the host and tumour resistance factors previously identified Clinical breakthroughs will be possible if we conduct clinical trials focusing on particular populations of patients. Both host specificities (such as co-morbidities, nutritional, immune status…) and tumour specificities identified through retrospective cohorts, translational and basic research results, will be integrated in the inclusion criteria of these trials. The targeted populations in the present Program do not usually meet the eligibility criteria in clinical trials launched by industrials, so it is necessary to design pragmatic trials adapted to medical constraints. This implies also that the ONCOLille Consortium includes a robust multidisciplinary team of methodologists, biostatisticians, regulatory affair specialists able to launch multicenter clinical trials. 2. To design clinical trials based on the evaluation of combined strategies Whereas combined strategies are frequently used, concomitantly or sequentially in practice, the vast majority of clinical trials are dedicated to one step of the cancer patient route, leading to some difficulties to integrate results obtained into the overall therapeutic sequence. Current therapeutic strategies result consequently more in a juxtaposition of proven concepts than in a well- balanced integration of these concepts during the longitudinal phase of cancer treatment. As examples, (i) clinical trials investigating the role of surgery and combined treatment including surgery require a specific expertise (oncologic surgeon with expertise in clinical research and medical oncology endpoints), (ii) clinical trials integrating survival endpoints combined with

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human sciences endpoints may lead to integrated patients‟ opinion in the treatment choice, (iii) ancillary translational research programs should be specifically designed to evaluate factors linked to resistance. Such trials are much more complex to conduct than classical trials investigating systemic treatment and deserve a strong expertise and important collaborations. Moreover, they are less frequently funded by industrial sponsors and thus need the help of academic groups, justifying the importance for the ONCOLille consortium to be labelled. 3. Methodology for the identification, validation and use of factors linked to tumour resistance The objective is to identify clinical, biological socio-economic and environmental factors associated with tumour resistance. We will use statistical methods adapted to the search for prognostic factors for loco-regional control by taking into account competing oncological events such as death, metastases and second primaries. In particular, the multivariate Cox model will be used to evaluate the impact of these factors, especially loco-regional control) on cause specific hazards. The Fine & Gray multivariate model will be used to evaluate their impact on cumulative incidence functions. These two approaches are necessary since the factors studied may behave differently on each component of progression-free or disease-free survival, often leading to contradictory results. We will also use innovative methods for the analysis of complex incomplete data (severity of toxicities, recurrent events during follow-up) in order to construct prognostic scores (MBU platform). Members of the EA2694 team have renowned methodological experience in the domain of data analysis in the presence of missing data, competing risks, and recurrent events. In order to identify factors of resistance, we will use the constituted cohorts within the scope of this project. The factors identified will then be validated with either re-sampling techniques or with data from external cohorts. Once validated, these factors could be taken into account in the selection and/or stratification of patients in phase I/II clinical trials (MBU platform), in order to optimizer the design of phase III clinical trials: stratification, matching or adjustment. Pathologies Head and neck, oesophageal, gastric, primary liver, lung carcinomas and malignant pleural mesothelioma Deliverables   

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M12-M30: Identification of prognostic scores M30-M36: Validation and publication of results M36: Integration of prognostic scores, into the design of clinical trials


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Task 3: Partnerships intensification, for accelerated integration of data coming from clinical, image-based, biological and pathological research programs to the bed side. Participants 

ONCOLille consortium management and scientific committee. The purpose of this task is to coordinate the knowledge and the diffusion of obtained results in ONCOLille programs and platforms in order to serve the global oncological community.

Objectives 

 



to speed up and reinforce the interaction between clinical, translational and basic researches to enhance patient survival through an accelerated and innovative tailored therapeutic approach to intensify research partnerships with industrial sponsors on cancers usually poorly studied: the aim is that ONCOLille consortium gains in visibility on such cancers to redirect some existing models of treatment resistance in order to accelerate (i) comprehension of the mechanisms involved in the targeted cancers and (ii) their translation into clinical applications to plan through the transversal and multidisciplinary scientific committee new collaborations and innovative approaches to reinforce research efficiency and production

Pathologies Head and neck, oesophageal, gastric, primary liver, lung carcinomas and malignant pleural mesothelioma Deliverables   

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M6-M36 : Identification of valuable results to be diffused M24-M60: Design clinical trials and fundamental research projects to enhance results in ONCOLille M0-M60: Diffusion of the knowledge through publications, national and international communications and local networks


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III.2.2.4. CONTRIBUTION OF HUMAN AND SOCIAL SCIENCES Task 1. Identify and model new factors of cancer over incidence and delay in diagnosis Participants 

V Christophe, JL Lefebvre, K Ligier, D Chevalier, A Berrier, P Meyer, P Camuzet, J Ton Van, B El Rassi, G Launoy, O Dejardin, T Leroy, M Seillier, J Foncel, S Dabo, O Torres, A Lamy, G Blanchard

Reducing the excess-incidence of cancer appears to be essential for the patients‟ vital prognosis and their quality of life. Various factors such as socio-demographical, socioeconomical, socio-educational, socio-cultural, and socio-professional factors already explain either this excess-incidence or late diagnosis for several types of cancers. However, these factors do not seem sufficient to fully explain or characterize patient delay or excess morbidity in, for example, UADT cancers. Some recent data, as well as classical theoretical models of health behaviour emergence, suggest that some socio-cognitive and emotional determinants may explain patient delay from a complementary point of view. Then, if one aims to modify patients‟ health behaviours to improve their vital prognosis, their quality of life, and to reduce social inequalities regarding health, it seems essential to reckon with patients‟ representations about health, as well as the contextual, emotional, and social determinants of their decisions and behaviours. Objectives 1. To identify new factors of risk of upper aero digestive tract cancers. There is an emergency to understand factors that lead to the very high regional incidence for the cancers targeted in this program. The current data on the known risk factors do not fully explain all the individual and collective determinants responsible for this excess-incidence of preventable cancers in the Nord – Pas de Calais region. Identifying new relevant factors of preventable cancers (socio-economical, psychological, behavioural, environmental and informational) and building interventional preventive researches related to this new dataset is a challenge for decreasing the excess-incidence and excess-mortality in this region of France. Knowledge of these factors will provide hope for better outcomes in the management of these lethal conditions. An econometric model of excess cancer incidence in the Region will be taken from the data collected at the patient level from the preceding program. This dataset will be supplemented by a survey conducted on cancer-free individuals. This econometric approach has the advantage of handling and testing together many factors that can potentially influence cancer incidence. Regarding methodology, multivariate and spatial statistical techniques that have been already applied to other fields of research will be used. This tool for primary prevention will thus complement the analysis of late diagnosis described above. In a second step, a multilevel and multidimensional model will be built to explain excess-mortality for these two criteria , i.e. excess-incidence and late diagnosis. Identifying New Risk Factors of upper aero digestive tract cancers, J Foncel, CPER Cancer Grant, 2011.  Team publications - Dabo-Niang, S et al. Mathematical Methods of Statistics 2007;4:1-20. - Dabo-Niang, S, et al. Stochastic Environmental Research and Risk Assessment, 2010; 4: 487-497. - Jouneau-Sion F et al. Journal of Econometrics. 2006; 133 2. To identify factors influencing treatment delays in targeted cancers and to reduce the inequalities to access to care. 

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On the basis of classical health psychology models, the main objective of this study is to assess if the consultation delay of a doctor after the first UADT cancer symptoms have occurred is linked to socio-cognitive and emotional factors, in complement of the previously cited factors. We propose to conduct a retrospective observational multicentre study, which does not imply any change of patients‟ medical care. Each patient with untreated UADT cancers may be included in this study, in six (public and private) health centres which take care of about 90% of UADT cancer patients of the North of France region. We expect to include 600 patients. The main evaluation criterion is the length of time between the occurrence of the first symptoms of the disease, and the first doctor consultation when these symptoms have been evoked by the patient. This patient delay is estimated 3 ways so as to optimize data validity. Medical, sociodemographical, socio-economical, socio-educational, socio-professional, geographical, sociocognitive, and emotional factors will also be assessed by means of (1) a case report form, (2) a questionnaire completed by the investigator in company with the patient, (3) a questionnaire completed by the patient himself, and (4) a taped semi-directive interview of the patient by a psychologist (for 80 patients only).  

Determinants of patients‟ delay in doctor consultation in upper aerodigestive tract cancers, V Christophe & JL Lefebvre CPER Cancer Grant, 2011. Team publications - Lefebvre JL, et al. J Natl Cancer Inst. 2009;101:142-52. - Rozniatowski O et al. Head Neck 2005 - Lefebvre JL et al. Int J RadiatOncolBiol Phys. 2009;73:1293-303.

Pathologies Head and neck and oeso-gastric cancers Deliverables  

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115

M36-48: Development of innovative tools and dataset analysis to explain individual and collective factors of preventable cancer over incidence (publications) M36-60: To better identify the factors influencing the delays in the three preventable cancers and to reduce the inequalities of access to care in order to have a direct impact on survival (measure 19 and 21 of French Cancer Plan II 2009-2013, M60: Define personalized accompanying action for (i) facilitating access to useful information for decision-making in health, (ii) facilitating access to care, (iii) offering support promoting preventive consultations of risk, M0-M60: knowledge‟s dissemination through publications, national and international communications and local networks.


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Task 2. Evaluation of the psychological, emotional and familial impact of clinical research in Oncology. Participants 

V Christophe, C Mariette, N Penel,A Desauw, C Duprez, E Fournier, P Antoine, E Constant, T Leroy, M Seillier, S Clisant, J Foncel S Dabo, O Torres, A Lamy, G Blanchard, T Leroy, L Vanlemmens, JL Nandrino, P Antoine

The difficulties when nursing a person with cancer have been subject to numerous researches, especially the diagnostic wandering, the impact of the disease and treatment on well-being, quality of life, emotional, psychological and family as well as socio-professional and financial sphere. The situation of the people with cancer as well as the difficulties encountered by their caregivers need to be more thoroughly investigated in order to promote interventional programs to suit the specific needs of both. The study of emotion regulation in caregivers „and patient‟s dynamic adjustment is fundamental to understand the disease evolution, cognitive and behaviour disorders. However, many stress management program are based on a relatively static stress-coping model, which has been used widely in studies of family caregivers. Under this cognitive theory, stress is conceptualized as a relationship between individuals and their environments, which they assess cognitively as exceeding or taxing their personal and social resources. Now, understanding the nature of the temporal dynamics of burden and care, and the emotional processes that underpin them, as well as individual differences in the patterns and regularities characterizing caregivers‟ and patient‟s adjustment remains one of the most important challenges in the study of care giving. Objectives 1. Psychological and emotional impact of the patient’s in clinical trials. The participation of patients in clinical studies in oncology occurs in most cases following the announcement of a bad news about their health (announcement of the diagnosis of cancer or a disease progression). The question then arises as a consequence of such an involvement in a context that could have undermined the psychological and emotional state of patients. Indeed, the participation in a clinical trial could generate in patients more positive effects (related to increased follow-up and the hope of improvement in their state of health through innovative treatments) than negative emotional effects, such as anxiety or depression (in conjunction with the uncertainty of the outcome of the situation, especially and even more if it is a randomized study). Despite the ambivalence of the possible consequences, few data are currently available on how patients live with their participation in a clinical study. The main objective is to compare the psychological and emotional consequences of such a treatment over time (chemotherapy or targeted therapy: effect on the type of treatment checked after the event) issued as part of a phase II or III clinical study (cases) to those of a standard delivered apart from the study (witnesses): quality of life, anxious and depressive symptoms, emotional and regulation strategies.  

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Psychological and emotional impact of the patient‟s participation in clinical trials , V Christophe & S Clisant INCa Grant (2009) Team publications - Christophe, V. et al . Psychology & Health 2008;23: 84-85. - Leroy, T. et al. New Drugs, in press, [http://www.ncbi.nlm.nih.gov/pubmed/19760365]. - Leroy, T., et al Contemporary Clinical Trials, in press [DOI 10.1016/j.cct.2010.09.003]. - Leroy, T et al Journal of Clinical Oncology 2009; 27, e17500.


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2. Emotional and cognitive impacts of surgery and peri-operative chemotherapies in the patient with operable gastric cancer and his/her partner. Few published data is currently available about the emotional or cognitive impact of treatment (surgery – chemotherapy) of a gastrointestinal cancer and in principle in operable gastric cancer. This innovative ancillary study, which is also a pilot and exploratory study, aims to gather a body of data in order to gain a better knowledge of the repercussions of this cancer and the specific methods of treatment not only on the patient, but also on his or her partner, the main natural carer. It also aims to obtain a better knowledge of how these repercussions develop in time by means of a longitudinal approach within a context in which the vital prognosis and toxicity of associated treatments are particularly severe. This study takes a dynamic and systemic approach to patient treatment taking into account the role of the family environment, and more specifically the husband/wife partnership. From this point of view, the observation of the dyadic adjustment of the experience of the patient and his/her partner in the course of the treatment seems extremely promising with regard to understanding the dynamics of the relational and emotional mechanisms at stake in a crisis situation such as discovering and treating ADCI. This is a matter of having a better grasp of the repercussions, benefits and costs of the different treatment schedules on the overall quality of life of the patients and their close carer, but also to stress the critical phases of this treatment by a longitudinal approach. The main aim of this exploratory ancillary study is to compare the development in time of the quality of life and the emotional and cognitive state of the patient, and his or her partner, depending on the treatment arm to which he or she was allocated. This study also aims to determine to what extent the understanding of the clinical trial, the perception of the disease, and the coping strategies mediate or moderate the effects of the treatment on quality of life and emotional state of the patient and his or her partner, and to measure over time the dyadic adjustment of the quality of life, emotional state, perception of the disease, and the coping strategies implemented by the patient-partner pair.  



phase II-III trial testing the role of primary surgery vs. primary chemotherapy in resectable signet ring cell gastric adenocarcinoma PI C Mariette, INCa PHRC grant 2011 Team‟s publications - Christophe, V., et al. Psychological Reports 2008 ; 103, 11-22. - Antoine, P et al. Journal of Health Psychology 2009; 14(8), 1156-1162. - Messager et al. Ann Surg. 2011;254:684-693. Piessen et al. Ann Surg. 2009;250:878-87.

3. To develop tools for assessing the quality of life of the patient and partner and evolution in time. Based on the experience developed in breast cancer, this modelisation will be applied to cancers targeted in the Program 1. A study of the quality of life of couples in which one person has cancer at a relatively young age seems to be innovative firstly because age has a non insignificant impact for patients (e.g. the desire to have children, educating very young children, sex life, professional future etc.) and secondly because there is very little empirical data available that addresses the role and the importance of close relatives and, more specifically, partners. Yet these close relatives who naturally take the role of caregiver on a day-to-day basis can find this very demanding. Gaining more in-depth knowledge about the experience of the partner is undeniably an advantage in terms of improving our understanding of the experience of the patient herself. This should no longer be a one-dimensional approach, but a dynamic and systematic approach to managing patients within their social and family environments. To our knowledge, there is no tool validated in French for assessing quality of life specific to this population that can really identify the preoccupations, difficulties and needs of these women and their partners during and after their treatment.

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The main objective was to create a questionnaire (with a patients‟ version and a partners‟ version) based on accounts of the experiences of young female patients with non-metastatic breast cancer and their partners. In order to guarantee a temporal perspective on the impact of the cancer from the time of diagnosis until the follow-up period after treatment has ended, four separate groups of 100 couples (that is, 400 patients and 400 partners) will be formed according to the patient's treatment route: 1) during chemotherapy plus or minus Trastuzumab; 2) during treatment with Trastuzumab plus or minus hormonal therapy; 3) during hormonal therapy only; and 4) during follow-up (after all treatment has ended). In order to test the psychometric properties (temporal reliability and concurrent validity) of the questionnaires for the patients and their partners, the participants will be randomly assigned to four sub-groups and invited to respond to: 1) the questionnaire to be validated (KALI), 2) KALI plus a quality of life questionnaire, 3) KALI plus anxiety and depression scales or 4) KALI once, and then a second time two weeks later. 





Subjective quality of life scale for young women with breast cancer and their partners, V Christophe & L Vanlemmens, INCa, Ligue Nationale contre le Cancer, Laboratoires pharmaceutiques Sanofi, Roche et Novartis Grant (2007-2009) Psychometric validation of a subjective quality of life scale for young women with breast cancer and their partners, V Christophe & L Vanlemmens , Ligue Nationale contre le Cancer ; Conseil Régional Nord Pas de Calais, Laboratoires pharmaceutiques Sanofi, Roche et Novartis Grant (2009-2012) Team publication: Vanlemmens, L. et al The Breast Journal, 2011in press.

Pathologies Head and neck and oeso-gastric cancers Deliverables 

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M6-M24: Compare the quality of life and survival of patients, their understanding of the implications of participating in a clinical research protocol, as well as their strategies and possible difficulties in emotional regulation during the clinical trial (publications). M12-M36: Identification and validation of therapeutic strategies to enhance or restore the quality of life of patients and partners (publications) M36-48: Development of innovative tools and dataset analysis to explain individual and collective factors of preventable cancer quality of life (publications) M60: Define personalized accompanying action for (i) facilitating access to useful information for decision-making in health, (ii) facilitating access to care, (iii) offering support promoting consultations therapeutic education of patients and their families to cope with the difficulties encountered. M0-M60: Diffusion of the knowledge through publications, national and international communications and local networks.


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III.2.3. EXPECTED RESULTS III.2.3.1. IN TERMS OF PRODUCTION This program will enable a qualitative and quantitative leap for the organization of research on the role of the tumour and host determinants in resistance to loco regional treatments, on the production of knowledge, and a transfer to clinical applications within clinical trials. The integrated axes of the Program will offer the possibility to reinforce the interaction between clinical, translational and basic researches with a common goal of enhancing patient‟s survival, quality of life and quality of care. The emerging projects and innovative results achieved will be communicated upon within the network of clinicians and researchers of ONCOLille using the dissemination mechanism scheduled to be developed in the ONCOLille program. Building on existing research groups, platforms, and clinicians of ONCOLille, this program will: 

Enable the rapid in vivo validation in Head and neck, oeso-gastric, primary liver and pleurapulmonary cancer patients the hypotheses and concepts generated in preclinical and in vitro tumour models. Conversely, it will enable the basic research teams to develop research programs aiming to understand the molecular mechanisms involved in the resistance to locoregional treatments



Enable the identification of therapeutic targets and development of therapeutic strategies and their validation in pre-clinical models and cohort studies - Identify molecular alteration/pathways that governs tumour and host resistance - Identify and validate targets to restore host anti-tumour immunity - Identify and validate targets to fight against tumour factors linked to resistance - Develop strategies to enhance therapeutic efficacy, such as anti-tumour targets - Define new therapeutic interventions and/or therapeutic sequences to improve tumour loco-regional controlled and patient‟s survival



Enable the development of clinical trials aiming at defining optimal therapeutic sequence per cancer according to tumour and host factors identified - Perform innovative trials, based on basic and translational research programs, to stimulate long lasting host anti-tumour immune response - Perform innovative trials, based on basic and translational research programs, to control and go around tumour parameters linked to resistance



Enable the reinforcment and acceleration, in parallel, of empirical identification of potential markers linked to tumour resistance based on a large amount of clinical and biological variables registered in established data base enrolling thousands of patients with head and neck, oeso-gastric, primary liver and pleura-pulmonary cancers.

Overall this program will have a major impact on:     

119

The field of experimental medicine through publications in high ranking journals The emergence and validation of novel concepts in human clinic leading to intellectual property protection The identification and validation of strategies, targets and drugs to reinforce host immunity and inhibit or turn around tumour factors linked to resistance Patients‟ care providing innovative therapeutic solutions, allowing to cure increase number of patients exposed to such disastrous disease Medical costs by a tailored therapeutic approach rather than global treatments for all patients


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Increasing recruitment in clinical trials to enhance research potential and quality of care Attraction of highly qualified scientists and MD within the SIRIC environment Attraction of students and postdoc abroad thanks to the scientific/clinical interface provided by SIRIC Attraction to donators and investors Attraction of biotechs and pharma to implant and develop within ONCOLille their clinical trials

    

III.2.3.2. IN TERMS OF DISSEMINATION OF KNOWLEDGE AND OF PROVISIONAL CALENDAR      

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Presentation at scientific congresses: 1 or 2 for each project line after 1 year Scientific publications: from year 3, more than 5 publications per year in journals with IF>15 Brevets: from year 3, more than one novel patent per year protecting concepts, strategies or drugs Increased recruitment in clinical trials from 15% in 2011 to 25% in 2015 Presentation of the results in CME programs already in place Training within the program plan of the SIRIC Lille-Nord de France, within and beyond the network


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III.2.4. FOCUS ON THE EMERGING RESEARCH ASPECTS THAT MAY BENEFIT FROM FUNDING OF THE

SIRIC To improve efficiency in loco-regional radiotherapy treatment, with the development of a transversal Monte-Carlo dose engine. Nick Reynaert, Thomas Lacornerie & Fabrizio Cleri – Department of Radiotherapy Centre Oscar Lambret & Institute of Electronic, Microelectronic and Nanotechnology (IEMN)) Over the last decade, technical possibilities in external beam radiotherapy have developed substantially (IMRT, Tomotherapy, robotic therapy, hadron therapy, image guided therapy, 4D radiotherapy…). In addition, important improvements have been made in treatment planning software, including options for inverse planning, and advanced dose calculation algorithms. A Monte Carlo dose engine is currently the only algorithm having the potential to meet this requirement, regardless of beam geometry and patient composition. The aim of present work is to introduce a QA system based on a standardized Monte Carlo dose engine able to calculate full 3D dose distributions for individual patients, using a DICOM interface (CT, tumour delineations, planned gantry angles, fields/segments, MU, etc). This Monte Carlo dose engine will be able to recalculate treatment plans for CyberKnife, Tomotherapy, IMRT and proton treatments. It will be extended to other dosimetric systems (laser therapy, hyperthermia...) For this purpose the MCDE system will be reprogrammed. MCDE is a full blown Monte Carlo tool based on the BEAMnrc/DOSXYZnrc user codes of the EGSnrc system, and has already been used intensively for benchmarking IMRT treatment planning for conventional Linacs, leading to over 20 scientific papers. No approximations are introduced and calculation time is kept within reasonable limits, by parallelizing the calculations on a cluster. Modelisation of morbi-mortality of primary liver cancer in France across stage of severity: evaluation of different strategies according to amount of screening and therapeutic resources (S Dharancy, P Mathurin): The objective of this project is to predict the impact of early screening and treatment on expected morbidity and mortality of patients by stage of gravity of the primary liver cancer and in the light of current practices. The project comprises three phases. The 1st phase requires the development of a Markov type compartmental model supplied by data obtained in studies published on the progression of primary liver cancer and the impact of available treatments, and mortality data by primary liver cancer from CepiDc. Assumptions on patients‟ distribution by stages will be based on data obtained from: (i) the Finistere registry (data published in Gastroenterologie Clinique et Biologique); (ii) an ongoing study from the register of Calvados (data supplied by the Dr. Isabelle Ollivier-Hourmand, CHRU Caen) and (iii) databases from the services of hepato-gastroenterology from consortium CIRRAL on primary liver cancer. This model will allow simulating the outcome of patients according to their degree of severity. The 2nd phase will consist in the validation of the model predictions over 1 year using epidemiological data from French Cancers registries collected by the FRANCIM network. This 2nd phase will be performed with a close collaboration with Mr Guy Launoy, director of the Calvados Cancer Registry. This phase will allow validating the robustness of the model. Once the model is validated, the 3rd phase will test the impact of different scenarios for screening and treatment on the morbidity and mortality of HCC. Our hypothesis is that early detection of HCC could increase patient access to curative treatment and hence their survival. Such information will help to define public health goals in the management of primary liver cancer.

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III.2.5. APPENDICES III.2.5.1. INTEGRATION WITHIN THE WHOLE SCIENTIFIC PROJECT – ARTICULATION WITH THE OTHER PROGRAMS

The Program 1 will achieve significant breakthroughs in the modelling of host and tumour resistance to initial loco-regional treatments. Even if initial resistance of cancer cells to treatment can explain early relapse, late relapse can only be explained by the persistence of a small population of cancer cells that remains dormant for a long period of time, defining tumour dormancy that is studied in Program 2. These 2 strongly linked programs will integrate biological and clinical research platforms, imaging and humans sciences developments, particularly in the field of comprehensive handling of the disease for the patient and the family (global care): since the same platforms are involved in the Programs 1 and 2, that will naturally reinforce links between the two programs. Morover, dissemination of knowledge will be directed towards patients, general and specialist practitioners, political authorities, healthcare providers and teaching activity on the same basis for the two Programs. Bringing together new data on the mechanisms of resistance and persistence to treatment in human tumours, biological models, imaging and clinical research will help to drive new studies in the field of adaptive and personalised medicine within a similar and interconnected approach

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III.2.5.2. PLANNING 2012 MONTHS

1

2

3

4

5

6

7

2013 8

2014

2015

2016

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scientific program 1: tumour and host resistance to loco-regional treatments Basic Research

Task 1 : Identification of molecular and cell mechanisms linked to resistance to treatments

Task 2 : Animal models to determine physio-pathological processes linked to primary or secondary tumour resistance

Signaling pathways in targeted cancers validated

Identification of molecular mechanisms associated to RTK and Mucin activity in targeted cancers validated

Key factors (tumoral et hostrelated) leading to tumour resistance identified in canine models

Specifically designed therapeutic strategy proposed in prospective clinical trials

Molecular markers identified from available induced and spontaneous animal models

Animal models developped for the study of resistance to treatment or angiogenesis in targeted cancers

Molecular mechanisms responsible for chemoresistance identified in targeted cancers

New molecular markers identified from available induced and spontaneous animal models Molecular mechanisms responsible for chemoresistance identified Drug testing on animal models

Start of clinical trials in humans

Animal models for other locations

End of clinical trials in humans

Translational Research Emerging biomarkers for targeted therapies Task 1 : Genetic, biological and pathologic factors linked to host and tumour resistance

Murine xenograft models

Methylation of mucin genes as predictive markers

Task 2 : Imaging techniques for early identification of tumour resistance

Protocol for multimodal imaging of molecules known as potential target of cancer resistance

Integrated multimodal imaging platform

Compendium of early diagnosis markers of cancer resistance Protocol for multimodal imaging of new drugs of cancer resistance

New imaging methodologi es

Protocol for in vivo imaging early diagnosis of patients towards cancer resistance

Clinical Research Start of identification of clinical predictors for resistance from existing data-bases and numerous ongoing trials Start of animal modelisation for resistance Task 1 : Identification of clinical tumour and host determinants leading to resistance to loco-regional treatments

End of identification of clinical predictors for resistance from existing data-bases and numerous ongoing trials

End of identification of biological and cellular predictions for resistance

Start of identification of biological and cellular predictions for resistance

End of animal modelisation for resistance

End of design clinical trials testing therapeutic strategies based on host/tumour predictors for resistance

Start of design clinical trials testing therapeutic strategies based on host/tumour predictors for resistance identified

End of integration of data coming fom research to the bed side

Start of integration of data coming fom research to the bed side Start of diffusion of the knowledge trough Beginning of idiffusion of the knowledge troughpublications, publications, national and national and international communications local networks international communications and localand networks

End of diffusion of the knowledge trough publications, national and international communications and local networks

Prognostic scores Start of identified identification of prognostic scores Start of validation and publication results

Task 2 : To tailor clinical trials with the aim to identify factors linked to resistance

Prognostic scores integrated into the design of clinical Results validated and publicated

Start of identification of valuable results to be diffused Task 3 : Parterships intensification for accelerated integration of data coming from clinical, image-based, biological and pathological research programs to bed side

End of identification of valuable results to be diffused End of design clinical trials and fundamental research projects to nehance results in ONCOLille

Start of design clinical trials and fundamental research projects to enhance results in ONCOLille Start of diffusion of the knowledge trough publications, national and international communications and local networks

End of diffusion of the knowledge trough publications, national and international communications and local networks

Human and social sciences Initiative tools and dataset analysis developed

Start of development of initiative tools and dataset analysis to explain individual and collective factors of Task 1 : Identify and model new factors of cancer over incidence and delay in diagnosis

Personalized accompanying actions defined Start of knowledge'dissemination trough publications, national and international communications and local networks

Task 2 : Evaluation of the psychological, emotional and familial impact of clinical research in oncology

Start of publications : quality of life and survival of patients, understanding of of clinical research protocol, emotional regulation during trials

End of publications : quality of life and survival of patients, understanding of of clinical research protocol, emotional regulation during trials

End of knowledge'dissemination trough publications, national and international communications and local networks Start of development of initiative tools and dataset analysis to explain individual and collective factors of preventable cancer over quality of life

1

2

3

4

5

6

7

2012

123

8

Initiative tools and dataset analysis developed Personalized accompanying action defined End of publications : therapeutic strategies to enhance o restore the quality of life of

Start of publications : therapeutic strategies to enhance o restore the quality of life of patients and partners Start of knowledge'dissemination trough publications, national and international communications and local networks

MONTHS

Factors influencing the delays in the three preventable cancers better identified

Start of identification of the factors influencing the delays in the three preventable cancers

End of knowledge'dissemination trough publications, national and international communications and local networks

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2013


2014

2015

2016

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III.2.5.3. BUDGET K€ HT

2012

2013

2014

2015

2016

TOTAL

EXPENDITURES Program 1 : Resistance

475

375

400

475

375

2 100

Staff for the current scientific projects Equipment Running Support for the emergence of new scientific projects

275 100 25 75

275

275

275

25 75

50 75

275 100 25 75

1 375 200 150 375

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25 75

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III.3. Tumour dormancy and persistence Program coordinator: Pr. Bruno Quesnel, MD, PhD, Inserm research team U837-E3 “Factors of persistence of leukemic cells”, Clinical Department of Haematology, CHRU Lille [email protected] and [email protected]

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III.3.1. MAJOR THEME OF THE PROGRAM III.3.1.1. SCIENTIFIC OBJECTIVES OF THE PROGRAM Many cancers respond to initial treatment, but most relapse, sometimes after decades. For instance, the recurrence of breast or prostate cancer frequently occurs through late metastasis after successful surgical removal of the primary tumour. In some tumour types, the entire cancer cell population has been exposed to an efficient systemic therapy. Acute leukaemia, for example, enters a complete remission phase after intensive chemotherapy. Nevertheless, relapses occur from a population of residual cells. Thus, recurrence in cancer is the rule rather than the exception, and targeting mechanisms that allow long-term persistence of residual cancer cells after treatment would likely improve survival. The biological factors that allow recurrence remain poorly understood. Initial resistance of cancer cells to treatment can explain early relapse (cf program1). However, late relapse can only be explained by the persistence of a small population of residual cells that remain dormant for a long period of time. This phenomenon of long-term persistence of cancer cells that do not grow is called tumour dormancy[1]. During this period, residual cancer cells remain in equilibrium with the host. [2]. Mechanisms that maintain this long-term equilibrium between residual tumour cells and host tissue or disrupt this equilibrium in favour of the tumour cells, leading to clinical relapse, have remained poorly understood. Few experimental models of tumour dormancy are available, and dormant tumour cells in humans are difficult to isolate, making scientific progress relatively slow. However, several experimental models have led to the discovery of mechanisms of dormancy. Reduced angiogenesis results in tumour dormancy in NOD-SCID models. The lack of an interaction between the microenvironment and the residual tumour cells can also lead to dormancy. Recent results have also demonstrated in new animal models that a balance exists between host anti-tumour immunity and dormant tumour cells and that these cells develop specific mechanisms of immuno-escape[3-5]. Tumour dormancy may also result from resistance to treatment. Many patients that undergo chemotherapy or targeted therapy have received treatment until progression, as discontinuation of therapy results in disease progression. However, most of the time (with the notable exception of CML) dormant tumour cells eventually escape from treatment and lead to relapse. Taken together, these findings present a complex picture of tumour dormancy. Thus, understanding the mechanisms of relapse must be investigated by a combination of several fields, which have in common their role in elucidating the long-term control of tumour cells.

III.3.1.2. METHODOLOGICAL BACKGROUND Assets of Lille’s teams Lille's teams have developed an expertise in the field of tumour recurrence and dormancy, especially in the fields of leukaemia and prostate cancer. 

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Inserm U837/IRCL builds several experimental models of tumour dormancy. These models are already available for the different projects and have already led to the discovery of news mechanisms of cancer persistence. The team is now one of the international leader in this field. In collaboration with the molecular biology department of CHRU Lille (Academic Hospital), Lille team's have focused on the genomic analysis of myeloid malignancies and has developed large-scale studies in collaboration with national and international clinical trial collaborative study groups, including ALFA, Phi-LCM, and GFM. This approach has led to the discovery of the prognostic role of several markers in acute myeloid leukaemia which have


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been quickly translated in the routine. Lille is now the French leader in genomic analysis of acute myeloid leukaemia, and the molecular biology department performs genomic screening for several academic and general hospitals in France. Prostate cancer, which is the prototypal example of tumour dormancy, is studied in Lille through the original approach of calcium channels at University. This methodology has led to outstanding publications like Cancer Cell, JCI etc. Prostate cancer is also now studied with stem cell models at Institut de Biologie de Lille. Malignant melanoma is a tumour that shows in few cases spontaneous regression and obvious signs of autologous anti-tumour immunity. This disease is also an attractive model to study the mechanisms that led to long-term equilibrium between dormant tumour cells and immune response. Inserm U837 is currently building melanoma dormancy models, and the dermatology department is one of the top recruiter of melanoma patients in France. Senescence is a key aspect of the long-term behaviour of resistant and dormant tumour cells. The Institut de Biologie de Lille has build a competitive team focused on senescence and oncogenesis.

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Highly competitive investigators (see appendix 10) Program 2 will gather several outstanding invetigators who have developed highly competitive scientific activivities in their respective fields. For instance, Claude Preudhome, with an h-index at 47 has published 190 papers, most of them as first or corresponding author in high ranking journals such as New England, JCO, Blood. Leukemia. Natacha Prevarskaya has published in Cancer Cell, JCI, Nature Review Cancer and is a world class expert in the field of calcium channel in cancer. Meyling Cheok authored in New England, Cancer Cell, JCI, Nature Medicine, Nature Genetics, JNCI. Bruno Quesnel published 115 papers in JCO, Blood, Cancer Research, Oncogene, Leukemia and is involved in both clinical and basic research and is a recognized expert in the field of tumor dormancy.

III.3.1.3. TEAMS, INSTITUTIONS AND INFRASTRUCTURES INVOLVED IN PROGRAM 2 Research laboratories:        

Inserm U837-E3 Head Bruno Quesnel Inserm U837-E4 Head Pierre Formstecher Clinical Department of Haematology, CHRU Lille Clinical Department of Dermatology, CHRU Lille UMR CNRS 8161 IBL Inserm U837-E4 Renata Polakowska INSERM U1003, Université Lille 1, Natacha Prevarskaya Inserm U837-E5, Guillemette Huet

Translational research poles:     

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TuDor Biotechnology; CEO Xavier Thuru Oncovet; Head Dominique Tierny EA4481 Lille2 Laboratory of cytogenetic Catherine Roche Lestienne The functional genomic facility of Université Lille 2. Martin Figeac


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Clinical medical departments: Service des Maladies du Sang, CHRU Lille, Bruno Quesnel, Service de Dermatologie, CHRU Lille, Laurent Mortier, Service d'Urologie, CHRU Lille, Arnaud Villers

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Human and sociales Sciences departments: Environment and professional pathologies department, CRDPD EA CHRU, Lille2

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III.3.2. MAIN TARGETS OF THE PROGRAM’S WORK III.3.2.1. BASIC RESEARCH Objectives The primary objective of the research program, which will be developed in the Comprehensive Cancer Centre ONCOLille is to understand recurrence. The program will specifically focus on mechanisms contributing to tumour dormancy and relapse after a period of complete remission. Specific goals    

To create new experimental models of tumour dormancy. To understand basic mechanisms of tumour dormancy To identify new predictive factors of relapse and translate them into the clinic To develop new drugs able to target dormant tumour cells and avoid or delay relapse.

General methodology To understand tumour dormancy and relapse and to test new drugs, new experimental models must be developed. Working with residual tumour cells from patients is currently an extraordinarily difficult task because these cells are undetectable in most patients, there are no well-characterized markers suited for their purification, and they must be studied in an environment that fully recapitulates host/tumour cell relationships. Our primary goal will be to establish relevant models using several tumour types. Next, the identified mechanisms of tumour dormancy will be investigated in a large cohort of patients as ancillary studies of a collaborative prospective clinical trial. Finally, drugs developed to target mechanisms that allow the long-term persistence of dormant tumour cells will be tested in experimental models of tumour dormancy and, if successful, patented and adapted to clinical development. In addition to this integrated program, we will perform large-scale genomic analyses of tumour samples collected in prospective clinical trials in order to isolate specific markers that predict relapse.

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Task 1 : Tumour dormancy and immunoevasion Participants    

Inserm U837-E3 Head Bruno Quesnel Inserm U837-E4 Head Pierre Formstecher Clinical Department of Haematology, CHRU Lille Clinical Department of Dermatology, CHRU Lille

Objective : to find new mechanisms of immune mediated dormancy Led by Bruno Quesnel, Inserm research team U837-E3 has developed a mouse model of tumour dormancy named DA1-3b in which residual acute myeloid leukaemia (AML) cells are in equilibrium with the host immune response [4, 6]. Mice in complete remission after one year manifested less than one thousand or at times less than one hundred dormant tumour cells. Thus, tumour dormancy in mice can result from a very small population of residual cells that persists in a balance with the immune system. Using this model, we have identified several mechanisms of tumour dormancy For instance, dormant tumour cells overexpress B7-H1 immunosuppressive molecules that inhibit T-cell activity through interaction with PD-1 and B7.1. Dormant tumour cells also deregulate several pathways, including the JAK/STAT and PI3K/AKT pathways, leading to cross-resistance between CTLs, TKIs, and chemotherapy[7]. These early results prompted us to develop additional models of tumour dormancy and to explore possible therapeutic developments. 

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New models of tumour dormancy (Carine Brinster): Our current model of tumour dormancy has led to the discovery of several new mechanisms of long-term persistence, but like other reported models, it also has severe limitations. The DA1-3b mouse model allowed us to study the mechanisms of immunoevasion developed by dormant tumour cells. However, few indications were obtained about the adaptation of the immune system during the period of tumour dormancy. We are now building an antigen-specific model in which dormant tumour cells express an artificial antigen. It will allow us to follow specific T-cells in vivo and determine how the adaptive immune response is modified by the continuous presence of tumour cells. The results would lead to new strategies of immunotherapy against dormant tumour cells Extension to solid tumours (Renata Polakowska and Bruno Quesnel): Another important limitation of the DA1-3b model is that it models dormancy of BCR-ABL leukaemia. It is likely that some of the mechanisms of tumour dormancy are tumour type-specific [8-9]. To explore the mechanisms of tumour dormancy in a more general perspective, we are currently building a mouse model of tumour dormancy in malignant melanoma.

Pathologies Acute Leukaemia, Chronic Myeloid Leukaemia, Melanoma Deliverables   

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(M12) New experimental models of melanoma dormancy (M24) Antigen-specific models of leukaemia dormancy (M36) Identification of new immunoescape mechanisms of tumour dormancy


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Task 2 : Tumour stem cells as factors of persistence and relapse Participants      

UMR 8161, IBL : Identification and characterization of prostate cancer stem cells Roland Bourette Inserm U837-E4 Renata Polakowska the Cellular Physiology Laboratory INSERM U1003, Université Lille 1, Natacha Prevarskaya Inserm U837-E5, Guillemette Huet UMR8161 CNRS, IBL, Martine Duterque Clinical Department of Dermatology, CHRU Lille, Laurent Mortier

Objectives Several models have shown that tumour dormancy may be due to the persistence of tumour stem cells. For instance, in experimental liver tumours, pancreatic tumours and skin papillomas, transient MYC inactivation induces most tumours cells to differentiate and undergo apoptosis, but some differentiated tumour cells remain tumorigenic and survive. In CML patients treated for years with imatinib, long-term complete hematological and cytogenetic remissions result, but BCR/ABL+ cells persist and can be detected at the molecular level. In patients treated for at least five years, attempts to withdraw imatinib led to molecular relapses. These persistent tumour cells are leukemic stem cells, which are resistant to tyrosine-kinase inhibitors. Thus, tumour dormancy occurs even in a malignant disease that is optimally controlled by continuous treatment because stem cells are not eradicated. In solid tumours, definitive demonstrations of tumour stem cells are still needed, but several groups have described a hierarchy of cell types, including some with stem cell properties. Thus, in many tumours, the dormant tumour cells may be stem cells. 

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Prostate cancer stem cells (Roland Bourette): Prostate cancer is the prototype of a dormant tumour. Patients with complete resection of the primary tumour or with non-resectable malignancies controlled by hormone therapy may carry disseminated tumour cells (DTC) for years without evidence of clinical progression. Characterization of the factors that control tumour stem cells in prostate cancer may help to delay tumour progression indefinitely [10]. Roland Bourette, of UMR CNRS 8161, is developing a new experimental prostate cancer stem cell model. The laboratory of Dr. Larry Rohrschneider (Fred Hutchinson Cancer Research Centre, Seattle, USA) has generated a transgenic mouse model with the unique property of expressing GFP in the apparent stem/progenitor cells of the embryonic and adult mouse by using the stem cell-specific promoter of s-SHIP [11][12]. In collaboration with Dr. Rohrschneider, Roland Bourette has recently demonstrated that s-SHIP promoter expression is also a marker for basal epithelial prostate cells exhibiting stem/progenitor cell properties. To pursue the characterization of PrSC and to extend this study to potential prostate cancer stem cells using the s-SHIP promoter expression as a marker, this project will be integrated in the SIRIC-Nord de France. Because of the similarity between stem cell profiles, the identification of regulatory pathways and specific markers should be useful for multiple tissue systems. Melanoma stem cells (Renata Polakowska): Another tumour type exhibiting the spontaneous behaviour of long-term tumour dormancy is malignant melanoma. Patients with metastatic melanoma may experience spontaneous tumour regression or prolonged dormancy of large metastases. We have already analyzed the role of the immune response in the control of melanoma cells in a mouse model (cf. supra). An interesting hypothesis is that the dormant melanoma cells are stem cells. In collaboration with oncodermatologist Dr. Mortier, we have initiated the collection of fresh tumours from melanoma patients and have established a protocol for developing primary melanoma cultures. Our preliminary data has identified new specific markers of melanoma stem cell that we are currently exploring. A comparative study of the expression of dormancy markers and stem cells will be undertaken in both human and mouse melanoma models. [13][14]. Finally, the ability of melanoma and dormant stem cells to escape immunosurveillance and their sensitivity/resistance to anticancer treatments will be explored.


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Role of intracellular calcium and membrane ion channels in human prostate physiology (Natalia Prevarskaya). 

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Prostate cancer is the prototype of dormant tumours. In many patients, the disease remain quiescent for years before being clinically significant. After radical prostate surgery, even patients with low PSA level and five years complete remission show DTC in the bone marrow. In addition, metastatic prostate cancer cells seem to use the same niche than hematopoietic cells in the bone marrow. These characteristics make this disease an attractive model to study tumour dormancy and recurrence. Recent studies have indicated that alterations in calcium homeostasis and in ion channels could play a central role in the regulation of processes such as proliferation, differentiation and oncogenesis. Every cell phenotype is characterized by a specific “calcium signature”, which is dependent on the kinetics, magnitude and sub-cellular localization of calcium signals. Therefore, quantitative and functional variations of ion channels disturb the physiological status of the cell and may lead to the development of a pathology called channelopathy [15]. Accumulating evidence has tended to demonstrate that the development of some cancers could also involve ion channel aberrations and, therefore, could be classified as channelopathies. The major scientific project of the Cellular Physiology Laboratory INSERM U1003 is to study channelopathies in prostate cancer [16-18]. The study of the role of intracellular calcium and membrane ion channels in the pathophysiology of the human prostate would help understand the mechanisms of progression in prostate cancer and escape from tumour dormancy. For this project, we have established two collaborations: one with Canceropôle Nord-Ouest tumour tissue bank (Pr X. Leroy) and the other with Urology service of Lille CHRU (Pr. A. Villers) in order to validate our results in human primary cells. We will also develop a collaboration with Roland Bourette lab in order to test calcium channels expression and function in prostate cancer stem cells.

Bone metastasis in prostate cancer (Martine Duterque): An important factor of tumour recurrence is metastatic dissemination. There is now evidence that this process occurs early in the history of malignancy, and disseminated tumour cells (DTC) may remain quiescent for long periods before becoming clinically symptomatic metastases. Understanding the metastatic process will contribute to the comprehension of tumour dormancy. Recently, ETS transcription factors have emerged as important elements in prostate tumorigenesis because recurrent translocations involving ETS genes were found in 50 to 80% of prostate cancer cases [19-20]. The abnormal over-expression of these ETS factors may disturb gene regulation in prostate cells. It is well established that disseminated tumour cells (DTC) and circulating tumour cells (CTC) exist in patients in complete remission. These cells are quiescent, related to stem cells and located in favourable environments, such as the bone marrow. These cancer cells are assumed to mimic some of the characters of normal cells present in the host organ by expressing genes that are usually expressed by osteoblasts and/or osteoclasts. This phenomenon, which is called osteomimicry, would apparently allow cancer cells to adapt to the bone marrow environment. Identifying genes involved in osteo-mimicry could be the subject of therapeutic targeting. 

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Our goal is to look for a link between “metastatic evolution” and “TMPRSS2-ETS fusion in primary tumour”. Martine Duterque‟s ERG gene study helped to establish its molecular transcriptional role and its association with skeletal formation. To achieve the goals outlined for this project, we have established two active collaborations: i) with the Canceropôle NordOuest tumour tissue bank (Pr Xavier Leroy) and Urology service of Lille CHRU (Arnaud Villers) to validate our hypotheses and identify genes in a human prostate cancer context and ii) with the U664 INSERM unit (Philippe Clézardin), experts in bone metastases, to develop mouse models of the induction of bone metastasis.


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Markers and mechanisms of drug-induced dormancy of colon tumour cells (Guillemette Huet): Dormancy can be activated by the microenvironment which produces restrictive conditions for proliferation of metastatic tumour cells. Dormancy can be also a mechanism for surviving chemotherapy. Entry into quiescence was observed in multiple myeloma with the proteasome inhibitor bortezomib. A key signalling feature of dormancy induced by microenvironment or therapy is the low ERK signalling and high p38 signalling that upregulates p53, NR2F1, BHLHB3 and inhibits c-Jun and FOXM1 (Sosa et al., 2011, Clin. Cancer Res.). Quiescent colorectal carcinoma cells are still unexplored (Buczacki et al., 2011, Brit. J. Cancer). 

Our team has previously studied drug-resistant HT-29 colon cancer cell subpopulations and clones obtained after chronic exposure to the clinically relevant anticancer agents 5fluorouracil (5-FU) and oxaliplatin (OXA) in terms of metastatic potential and drug-resistance (Dessein et al., 2011, Cancer Res.). Recently, we have started to study their properties of cancer stem cells and dormancy in collaboration with another team of our research centre (Dr R Polakowska). In this project, We will first identify the markers and mechanisms associated to the induction of quiescence of colon carcinoma cells by 5-FU treatment, and 2- We will then analyse the expression of the markers identified with the cell model, in samples of human liver metastases and adjacent liver tissues resected from two groups of metastatic colon cancer patients (treated or not by neo-adjuvant chemotherapy prior to surgical resection)

Pathologies Prostate Cancer, Melanoma, Epithelial cancers Deliverables    

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(M24) Mouse model of prostate cancer stem cell (M36) Identification of stem cell characteristics in dormant melanoma cells (M36) Characterization of calcium channels in prostate and melanoma cancer stem cells (M24) Identification of drug resistance mechanisms in dormant tumour cells


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Task 3 Tumour dormancy and senescence: Participants  

Team involved: UMR CNRS 8161, Corinne Abbadie, Albin Pourtier INSERM U837-E3

Objectives: to explore the senescence program in dormant tumour cells Numerous reports claim that senescence corresponds to an irreversible growth arrest mechanism that cancer cells have to bypass to generate tumours. However, the cell-cycle arrest associated with senescence is not irreversible in all cell types, notably in epithelial cells that are at the origin of the most frequent cancers in humans. Although they display all the characteristics of senescent cells, normal human epithelial cells that have reached the senescence plateau can spontaneously reactivate a mitotic process to generate so-called post-senescence (PS) emerging cells, which are transformed and able to form skin hyperplasias in nude mice. Data from our group suggest that the oxidative DNA damage encountered by senescent cells could be the mutagenic motor underlying this neoplastic emergence [22-23]. Therefore, at least in these cell types, rather than being tumour suppressor, senescence would represent a steadystate, during which cancer-promoting mechanisms occur. Moreover, we and others have shown that fibroblast senescence is associated with a complete change in the cell secretome. Some of our current analyses show that this secretome enhances PS emergence and confers new migratory and invasive properties to the PS-emergent cells. In the context of tumour dormancy, it must be highlighted that several anticancer radio and chemotherapies act through the generation of oxidative stress and senescence induction. Therefore, one can speculate that after an anticancer treatment, some residual tumour cells may persist in the organism for a long time in a dormant senescent state and that tumour growth and disease may recur through a mechanism similar to the post-senescence emergence we have characterized in keratinocyte cultures. For ONCOLille, we propose to use the in vitro model of post-senescence emergence of neoplastic keratinocytes to study i) the role of senescenceassociated oxidative stress in the emergence from normal or drug-induced senescence; ii) the importance of programmed cell death (including apoptosis and autophagic cell death) resistance acquisition for carcinoma initiation, and the possibility that tumours may acquire this resistance during normal or drug-induced senescence; and iii) the importance of changes occurring in the normal or drug-induced senescing microenvironment, notably to the fibroblast secretome, in terms of promoting carcinoma initiation and conferring malignant properties Pathologies Epithelial tumours, Acute Leukaemia, Melanoma Deliverables 

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(M36) Identification of senescence mechanisms in dormant tumour cells


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III.3.2.2. TRANSLATIONAL RESEARCH Task 1 : Predicting relapse Participants     

Inserm U837-E3 Meyling Cheok (Pharmacogenomic) Laboratory of Haematology CHRU Lille: Claude Preudhomme Laboratory of cytogenetic Catherine Roche Lestienne Service des Maladies du Sang CHRU Lille, Bruno Quesnel The functional genomic facility of Université Lille 2. Martin Figeac

Objective: to find molecular markers predictive of relapse Understanding the mechanisms of tumour dormancy and relapse require experimental models to decipher the extreme complexity of these phenomena. A different approach with potentially faster translation into the clinic is to determine predictive markers of relapse at diagnosis. Claude Preudhomme has focused on the genomic analysis of myeloid malignancies and has developed large-scale studies in collaboration with national and international clinical trial collaborative study groups, including ALFA, Phi-LCM, and GFM. This approach has led to the discovery of the prognostic role of several markers in acute myeloid leukaemia, such as IDH1 and IDH2, AML1, and CEBPA [24-27]. The validation of minimal residual markers is also an important part of the team's work, and it is rapidly translated into the clinic and has led to outstanding publications, including New England Journal of Medicine, JCO etc. The team has now moved to high throughput techniques like CGH and SNP arrays and next-generation sequencing (NGS). In addition, a large tumour bank (Tumorothèque CHRU de Lille) has been filled with every sample of AML, CML, ALL, and MDS from our region and the national clinical trials for these diseases. A recent and important development in the project began when Meyling Cheok arrived from St Jude Hospital (Memphis) with an expertise in the pharmacogenomics of ALL [28-31]. Meyling Cheok, who received a permanent position in Inserm U837-E in 2009, is now conducting a new study using transcriptomic analysis of AML cells exposed to cytotoxic drugs. The profile will be translated into future clinical trials to stratify patients based on primary resistance. It will also offer leads to be explored in our models of tumour dormancy. 

The availability of this recognized expertise and integrated platform will allow us to rapidly validate the hypotheses raised in our experimental models of tumour dormancy and relapse. Conversely, the identification of molecular markers that appear to influence the long-term evolution of myeloid malignancies will be tested in experimental models to understand their contribution to the persistence of minimal residual disease.

Pathologies Acute Myeloid Leukaemia, Chronic Myeloid Leukaemia Deliverables 

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M12, M24, M36, M48, M60 New predictive markers of relapse in AML and CML


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Task 2 : Targeting dormant tumour cells Participants        

TuDor Biotechnology; CEO Xavier Thuru Oncovet; Head Dominique Tierny OCR, Head Dominique Tierny Inserm U837-E3 Head Bruno Quesnel Inserm U837-E4 Head Pierre Formstecher EA4481 Régis Millet Group, leader of pharmaceutical chemistry, and Philippe Chavatte Group, leader of Drug design, Faculty of Pharmacy Benoit Rigo EA 4481, Laboratoire de Pharmacochimie, Ecole des Hautes Etudes d‟Ingénieur EA 4481 Jean-François Goossens “Interdisciplinary Research Group of Therapeutic Innovation” (director: Pr. J-P. BONTE)

Objective: to design drugs that target immunoescape mechanisms in dormant tumour cells The objective of this project, in collaboration with a pharmaceutical company [Regis Millet] and a drug design team [Philippe Chavatte], is to develop small molecules that block the interaction between B7-H1/B7-1 or B7-H1/PD-1 and allow the restoration of the host anti-tumour immune response against dormant tumour cells. We have already defined several structures that are able to interact with B7-H1 and B7.1. We developed in vitro models of resistance to CTLs via B7H1 and B7.1 and an in vivo model of tumour dormancy [Bruno Quesnel]. These models will be used to evaluate the capacity of the new compounds to restore the immune response and the capacity of the host to eradicate dormant tumour cells. We hope to develop several molecules from different chemical families with strong potentials to block the different interactions between B7.1/B7-H1/PD-1. If successful, these molecules will undergo pharmaceutical development with the major objective of blocking immunoescape mechanisms in patients in cancer remission and allowing the eradication of, or at least the long-term control of, minimal residual disease. Integration of additional teams involved in immunomodulation in cancer into the SIRIC program will also provide an opportunity to cross-test these different approaches. These approaches could be tested in all tumour dormancy models developed. In addition, to this specific project, we will use also our tumour dormancy models to test the ability of new drugs to eradicate the minimal residual disease. Several pharmaceutical teams focused on drug synthesis have already a large portfolio of original compounds that will be tested in these models in a Go/no Go strategy. If successful, compounds will be tested in veterinarian models with ONCOVET and TuDor Biotech. Biotech partnership These therapeutic approaches will be developed in partnership with Biotech Companies supporting the SIRIC: TuDor Biotech is a start-up company created by Xavier Thuru and Bruno Quesnel, focused on drugs targeting dormant tumour cells.  ONCOVET is a veterinary clinic dedicated to the treatment of animal cancers, and as such will be able to set-up clinical trial to test new drugs against dormant tumour cells.  OCR (Oncovet Clinical Research) is a private Contract Research Organization that proposes validated animal models of spontaneous diseases. Xavier Thuru (TuDor Biotech), Bruno Quesnel (Inserm U837-E3), and Dominique Tierny (ONCOVET, OCR) will elaborate tools to detect minimal residual disease in dog with spontaneous breast 

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carcinoma or lymphoma; which mimick human tumour histology and behaviour. Dormant tumour cells will be isolated from dog‟s bone marrow. This will offer a new model to test new drugs designed to target dormant tumour cells in clinical trial with large animals. Pathologies Acute Myeloid Leukaemia, Chronic Myeloid Leukaemia, Malignant melanoma, Prostate cancer Deliverables  

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(M18) Testing new drugs targeting B7-H1 in experimental models of tumour dormancy (M24)Testing new drugs on minimal residual disease in veterinarian cancers.


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III.3.2.3. CLINICAL RESEARCH Task 1 : Accelerating the clinical developments of dormant tumour cell-targeting drugs Participants    

Laboratoire d'hématologie CHRU Lille, Claude Preudhomme Service des Maladies du Sang, CHRU Lille, Bruno Quesnel Service de Dermatologie, CHRU Lille, Laurent Mortier Service d'Urologie, CHRU Lille, Arnaud Villers

Objectives Data from genomic analyses of myeloid malignancies are rapidly accumulating with the improvement of high throughput techniques like WGS or WES. Validation of these new markers will be done in clinical trials from collaborative study groups. If the drug development process from the SIRIC is successful, we will have several dormant tumour cell-targeting drugs to enter into clinical development. The different clinical departments of the SIRIC are already strong contributors of large academic- or industry-sponsored teams. This will facilitate the design of phase I trials. Pathologies Acute Myeloid Leukaemia, Chronic Myeloid Leukaemia, Prostate Cancer, Melanoma Deliverables  

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(M36) To develop Phase I clinical trials with drugs targeting dormant tumour cells developed by the Drug design network of SIRIC (M48) To develop new stratifications in phase III clinical trials of ALFA, GFM, Phi-LMC collaborative study groups with the molecular and pharmacogenomic markers characterized by SIRIC's teams.


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III.3.3. EXPECTED RESULTS  

To establish Lille as a reference centre for tumour dormancy and predictors of relapse To develop new drugs that delay or avoid relapse by converting cancer in a chronic disease.

We hope to establish in Lille an internationally recognized center of excellence in the field of tumor dormancy and relapse. Priority will be given to the testing of hypotheses generated from one experimental model across other available systems to generate more general and broadly applicable results (e.g. the role of B7-H1 in tumor dormancy outside the DA1-3b model and the role of membrane ions channels in drug resistance). Governance through the SIRIC will be critical for such coordinate effort. The strength of Lille's research teams in translational research will enable us to reinforce the current highly competitive activity of predictive markers in myeloid malignancies. Combination of this already recognized activity with data from pharamacogenomic will allow us to accurately precise the behavior of the leukemia disease with time and to give the necessary tools to validate hypotheses obtained in experimental models of tumor dormancy. The SIRIC will also give us the opportunity to create an entirely new network between pharmacological, fundamental, and translational teams with biotech companies. This network will specifically benefit from the coordination by SIRIC as such collaborations between teams covering such different fields from chemistry to veterinarian models need tight governance. Our goal is to design and isolate several new drugs targeting dormant tumor cells that could enter into Phase I trials

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III.3.4. FOCUS ON THE EMERGING RESEARCH ASPECTS THAT MAY BENEFIT FROM FUNDING OF THE

SIRIC MODELLING RECURRENCE Nicolas Penel (Centre Oscar Lambret, Universités Lille 2 & Lille – Nord de France) Several scenarios of post-therapeutic surveillance mechanisms (examination modalities and their rhythm) will be proposed. The incidence of events of interest accessible to an effective treatment will be estimated for the different scenarios. Using Monte-Carlo or Markoviens models, we will gauge optimal conditions of surveillance that maximise the clinical benefit in terms of quality adjusted life years (QALYs) and that minimise costs to the society (Penel 2008). This modelling work uses the Bayesian approach (Penel 2009). The factors introduced in the model (probability of events, management and treatment costs, cost of treating a recurrence, survival data, quality of life data) will be the purview of the SIRIC. The decision tree diagrams (base-case analysis) will include data observed in order to estimate probabilities of transition between different states of health and related costs. Costs will be calculated in the context of the society (including direct and indirect costs and possibly spot costs arising from the occasion, e.g. mobilising material resources such as CT scanners or MRI. Survival and quality of life data will be included in the form of QALYs. The result of the base-case analysis will be subjected to multifactor analyses of sensitivity involving observed variations of the various elements introduced in the model. For frequencies and numerical values, the analysis of sensitivity is based primarily on the Monte-Carlo method and for survival data on Markoviens models. The data obtained from this modelling work will be a decision-making assistance tool for health policies and will extend data obtained from randomised clinical trials. The originality of this modelling work done by ONCOLille is that much of it will be based on information gathered from a real population and in a given geographic sector. The usual weakness of modelling is the use of data obtained from multiple heterogeneous sources such as clinical trials, retrospective studies or estimations on small samples.

POST TREATMENT REINSERTION Sophie Quinton-Fantoni (CHRU de Lille, Universités Lille 2 & Lille – Nord de France) Progress in the treatment of cancers has resulted in a continuing increase in the number of patients in remission in France (more than 60% of patients are in remission after 5 years, even though the figures of course depend on the type of cancer, the treatment and the stage of the disease at which treatment started). Questions of socio-professional insertion and return to work after treatment are thus being asked more and more frequently. Professional reinsertion is an important and unanimously recognised factor in the overall management of these patients. It affects their quality of life, financial security, re-establishing a stable social environment, a feeling of being normal and control over their lives. The socio-professional consequences of cancers are undeniably related to the severity of the disease and to its co-morbidities, to the extent of treatment and its side effects, to the system of social protection, but also to socio-professional inequalities and psychological, familial, social and professional disparities (work load, environment, etc.) that determine the capacities of patients to act. In addition, the longer the employee's sick leave, the more the relation with his work become weaker, and the fewer the chances of resuming work on good, if not optimal conditions. This is truer since cancer patients receive little or no information about their work and its resumption. In the context of "living with" cancer and improving the quality of life of cancer patients, it is crucial to favour return to work as soon as possible in order to minimise the degradation of working conditions or a feeling of "not belonging" to the society. At a time when support care is increasing, there remains inquestionable work to be done in assistance and rehabilitation to return to work, as shown by the 2009-2013 national Cancer Plan II.

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The Lille occupational medicine team is now working with oncology groups on the issue of socioprofessional reinsertion for breast cancer patients. In addition, the dual competence of our team in law and medicine (member of the Centre of Law and Perspectives of Law, EA 4487) has enable it to examine the responsibility of employers concerning the health of their employees at the international and legal levels; this involves both their obligations of job changes and reclassification and safety obligations that are a corporate burden in health and workplace safety. The aim will be the preparation of a genuine strategy of socio-professional reinsertion by including its determinants resulting from collaborations with different teams

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III.3.5. APPENDICES III.3.5.1. PLANNING 2012 MONTHS

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2013 8

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Scientific program 2: tumour dormancy and persistence Basic Research Antigen-specific models of leukaemia dormancy

New experimental models of melanoma

Task 1 : Tumour dormancy and immunoevasion

Stem cell characteristics in dormant melanoma cells identified

Mouse model of prostate cancer stem cell

Task 2 : Tumour stem cells as factors of persistence and relapse

New immunoescape mechanisms of tumour dormancy identified

Drug resistance mechanisms in dormant tumour cells identified

Calcium channels in prostate and melanoma cancer stem cells characterizated Senescence mechanisms in dormant tumour cells identified

Task 3 : Tumour dormancy and senescence

Translational Research New predictive markers of relapse in AML and CML

Task 1 : Predicting relapse

New predictive markers of relapse in AML and CML



New predictive markers of relapse in AML and CML New drugs targeting B7-H1 tested in experimental models of tumour dormancy

Task 2 : Targeting dormant tumour cells

New drugs tested on minimal residual disease in veterinarian cancers

Clinical Research Start of Phase 1 clinical trials with drugs targeting dormant tumour cells developed by the Drug design network of SIRIC

Task 1 : Accelerating the clinical developments of dormant tumour cell-targeting drugs MONTHS

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7

8

Start of development of new stratifications in phase 3 clinical trials of ALFA, GFM, Phi-LMC collaborative study groups with the molecular and pharmacogenomic markers characterized by SIRIC's

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2012

2013

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2016

III.3.5.2. BUDGET K€ HT

2012

2013

2014

2015

2016

TOTAL

EXPENDITURES Program2 : Dormancy Staff for the current scientific projects (3 post doctoral positions) Equipment Running Support for the emergence of new scientific projects

141

420

330

270

320

250

1 590

220

220

200

180

180

1 000

20

140 120

50

330

70 30

30

20

70 20

100

80

50

50


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IV.

National and international collaborations program

IV.1.

Role in regional and national clinical research

Lille is funding member of the Cancéropôle Nord-Ouest (CNO) which was set up under the first “plan cancer I” in 2003. CNO includes the cancer research forces in the four regions of Nord-Pas de Calais (Lille), Picardie (Amiens), Haute Normandie (Rouen) and Basse Normandie (Caen). CNO was evaluated by AERES in 2011 and considered as the best canceropole in terms of added value and granted for the next four years (2011-2014). The five scientific programmes currently developed by CNO are: “1-From development and validation of prognostic and predictive biomarkers to therapeutic innovation”, “2Onset and evolution of tumours in malignant blood disorders”, “3-Multimodality targeting in oncology”, “4-Cancer and Neurosciences” & “5Cancer, Individuals and Society”. More than half of the basic research teams of CNO are located in Lille, and ONCOLille cancer research leaders play a key role in the coordination of CNO programmes (Yvan De Launoit, Claude Preudhomme, Eric Lartigau and Veronique Christophe in programmes 1, 2, 3 and 5 respectively). ONCOLille clinicians and researchers obtained 53 grants from INCa since 2005 (13M €) and are well identified leaders of collaborative projects supported by INCa in various fields, like:        

Christophe Mariette in oesogastric cancers Philippe Mathurin in hepatocarcinoma Jean-Louis Lefebvre in head and neck cancers Claude Preudhomme in translational research on acute leukemias Bruno Quesnel in tumour dormancy Natacha Prevarskaya in the growing field of calcium channels and cancers Fabrice Soncin in angiogenesis Veronique Christophe in human sciences

Importantly, the cancer register of Lille and its area, created in 2009, is involved in a growing number of local, regional and national research projects, supported by various institutions: C2RC, the Regional Cancer Network and Région Nord Pas de Calais for regional projects and INCa and IReSP (national research institute in public health) for national projects. Specific collaborations are related to the two scientific programs For Program 1 Regional organizations for the management of primary liver cancer (networks: CIRRTRANS, interregional network CARNOR, S Dharancy), oesophageal cancer (OESO data base C Mariette), lung and mesothelioma cancers (CBNPC 59-62 database A Scheerperel) Partnership with regional or national scientific societies: FFCD, UNICANCER, FRENCH, SFCD, SPLF, ERS, IFCT, GORTEC, GETTEC … A large regional program is ongoing with the radiation oncologists in Nord-Pas de Calais, Picardie and Champagne Ardennes. This program based on a collaboration with the Aquilab society (see appendices) will implant strict quality controls in the field of treatment safety and prostate tumour contouring. This CRNOR program is financed partly by the INCa (one post of quality officer) and by the Regional Councils.

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For program 2 Creation of a regional Acute Myeloid Leukemia Observatory, bringing together all oncohematologists working in the Nord Pas de Calais Region (Dunkerque, Boulogne, Arras, Lens, Valenciennes and Roubaix general hospitals. This observatory collect biological, clinical and therapeutic data of almost all patients treated for AML in the region. 275 patients have already been included during the last two years. Oncohematologists are coordinators or participants in many large-scale studies in collaboration with national and international clinical trial collaborative study groups, including ALFA, Phi-LCM, and GFM.

IV.2.

International networks and collaborations

For program 1 Teams involved in program 1 developed numerous bilateral collaborations with national and international research teams in their individual fields Main coooperations alre listed below : International recognition of clinician leading European networks in particular in oesogastric cancer (C Mariette), liver determinants leading to cancer resistance (P Mathurin, S Dharancy), tumoral determinants of resistance in head and neck carcinoma (JL Lefebvre) and mesothelioma (A Scherpereel). International clinical collaborations based on a strong national leadership and clinical trials involving EORTC, ELCWP etc… Partnership with numerous pharmaceutical companies on national and international clinical trials: Nestle, Merck, GSK, Amgen, Boehringer-Ingelheim, Lilly, Roche, IRIS-Servier, Daichi, EISAI… For the adaptation of treatment to advanced and recurring tumours, collaboration in imaging is active with colleagues from Saint Luc University, Brussels (Pr V. Gregoire), Rotterdam (Pr P. Levendag) and with the two CyberKnife Centres at Mount Vernon Hospital, Northwood and Royal Marsden London, UK. Accuray is the first radiation oncology company that manufactures and sells the CyberKnife and the TomoTherapy systems. Since 2007, Accuray has established a continuing collaborative partnership with Oscar Lambret cancer centre. Accuray has closely worked with the Radiation Therapy department for testing and evaluate specified products and technologies under development for the CyberKnife. Accuray has co-developed with Oscar Lambret cancer centre an international clinical study with Dr. Mirabel as principal investigator. The study is currently enrolling patients. Its anticipated end is in 2015. Oscar Lambret cancer centre has developed and implemented a customer training program for the CyberKnife system and is now one of the two CyberKnife training centres in Europe.” Program 2 Teams involved in program 2 developed numerous bilateral collaborations with national and international research teams in their individual fields (stem cells, dormancy, senescence,

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angiogenesis…). The team working on calcium channels and cancer (Natascha Prevarskaya) is a member of the recently granted (October 2011) Marie Curie Initial Training network on Ion Transport Proteins in Control of Cancer Cell Behaviour (IonTrac) Claude Preudhomme is a member and investigator (WP12 and WP13) of LEUKEMIANET (FP6), a cooperative network for advancements in leukemia-related research and health care, associating the leading leukemia trial groups, their interdisciplinary partners (diagnostics, treatment research, registry, guidelines), industry and SMEs across Europe. He is also a very active member of European interlaboratory networks investigating the reproducibility of molecular methods and trying to define standard procedures (IRON study coordinated by Roche Molecular Biology to evaluate NGS methods, EUTOS network of national and regional reference laboratories) Platforms Occupational medicine: Since the 1990s, partnerships have been developed with colleagues from Canada in the field of Research on Occupational Integration and the Psychosocial Environment of Work (Louise St-Arnaud & Anne-Marie Laflamme, Charles de Koninck law faculty, Université Laval, Quebec). In June 2009, a French-Canadian symposium was held with 400 experts participating. Oncovet is the coordinator and partner 1 of ANCABOR, a European biotechnology project supported by the EUROTRANS-BIO 4th Transnational Call published on 7th January 2009. This 3 years project associates 3 academic teams expert in biomaterial conception and evaluation from France (Inserm U1008 and CNRS UMR8207 in Lille) and Germany (REPAIR-Lab, University of Mainz), one German SME (Curazan AG) and Oncovet to develop and evaluate functionalized bioceramic implants liberating anticancer drugs in a spontaneous model osteosarcoma in dogs.

IV.3. Strategy of the SIRIC for national and international collaboration The existing national and international collaborations will be reinforced in all the fields: basic research, clinical research and technological developments. A national observatory of oesogastric cancers, including clinical, biological and pathological data, will be created in the forthcoming year with the support of INCa; Owing to its visibility in the field in specific cancers (oesophagus, head and neck, mesothelioma and primary liver cancer), particularly frequent in Lille and its region, ONCOLille should become a main player in European clinical trials concerning these cancers One of our objectives is to create an outstanding and internationally recognized centre of research on tumour dormancy. To reach this goal, international collaborations at the highest level will be sought. Bruno Quesnel already started collaboration with mathematicians working on modelling dormancy at the Center of Cancer Systems Biology (CCSB, Tufts University, Boston, MA). CCSB hosts one of the world leader groups working on tumour dormancy and is supported by the NCI Integrative Cancer Biology Program.

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The already existing international visibility of Claude Preudhomme and his coworkers in translational research on acute myeloid leukaemia will be further developed in the next three years:  



The IRON project will be pursued. A project focused on the personalized follow-up of residual disease in acute myeloid leukemia using NGS techniques is in preparation with European partners to apply to the forthcoming ERA-NET TRANSCAN call for proposals (December 2011). The Cancer and Leukemia Group B (CALGB), a national clinical research group sponsored by the National Cancer Institute, will be approached to share data and develop common projects, in particular in the field of AML in aged patients.

With the specific assets provided by Oncovet and Oncovet Clinical Research (large access to animals with spontaneous non-induced tumours, canine and feline tissue bank, histological platform), ONCOLille Consortium should become a major player in clinical research on animals with spontaneous tumours. Oncovet Clinical Research ambition for the next five years is to develop collaborations at both the national and international levels: 



Oncovet Clinical Research will enter the national working force on experimental histopathology and virtual microscopy created in 2011 by the Canceropole Conference and INCa and propose the creation of an active network involving the complementary forces available in France in the field of spontaneous tumours animal models. Oncovet Clinical Research intend to develop research projects with pharmaceutical companies with EU support (FUI programme) and to start collaborations with the Comparative Oncology Trials Consortium launched by the National Cancer Institute in order to better understand the biology of cancer and to assess novel treatments using pet animals (https://ccrod.cancer.gov/confluence/display/CCRCOPWeb/Home)

Deliverables and planning:       

M6 International collaborations Plan Approved M12 Observatory of oesogastric set up M12 Frame of the cooperation with comparative Oncology trial consortium defined M16 Animal spontaneous tumours models international research network set up M18 first report national and international collaboration M10 - M58 (one yearly): International Resistance & Dormancy Conference organized M24, M36, M48 Report on animal spontaneous tumours models international research network published 2012 MONTHS

1

2

3

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5

6

7

2013 8

2014

2015

2016

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

National & international collaborations program First international Resistance & Dormancy Conference

International collaborations Plan approved

International Resistance & Dormancy Conference

National and international collaboration first report

Frame of the cooperation with comparative Oncology Trial consortium defined

1

2

3

4

5

6

7

2012

145

8

International Resistance & Dormancy Conference International Resistance & Dormancy Conference

Animal spontaneous tumours models international research network set up Report on animal spontaneous tumours models international research network published

Observatory of oesogastric set up MONTHS

International Resistance & Dormancy Conference

Report on animal spontaneous tumours models international research network published

Report on animal spontaneous tumours models international research network published

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V.

Partnership and valorisation strategy

V.1. Strategy and priorities The work handled within ONCOLILLE will give a conclusive opportunity to reinforce the impact of the research led by the collaborating teams, in terms of academic visibility, industrial economic and social value for the benefit of the patients,.. Outcomes research and a more structured clinical management system will improve patient care in the short term and participation in novel interventional studies is also of potential benefit for the patient. Besides, the overall objective of the valorisation strategy will be to ensure ONCOLILLE as a leading European Oncology centre over the next five years. To meet this priority, the following key strategic actions will therefore be: 1. To transform research investment in IP 2. To develop of an effective partnership strategy with industry - By reinforcing existing partnerships - By Developing new partnerships 3. To develop a communication strategy that will enhance the SIRIC‟s attractiveness and profile

V.2. Strategy implementation V.2.1. THE TECHNOLOGY TRANSFER ORGANISATION IMPLEMENTED IN THE SCOPE OF ONCOLILLE ONCOLille will rely on the strong and long lasting partnership and know how already developed by its mains partners in the field of technology transfer: the SATT Nord de France Valo and Eurasanté. These bodies will have a clear assignment, aiming to boost the technology transfer and the economic added value of the ONCOLille research programs

V.2.1.1. THE FRAME OF THE COOPERATION WITHIN LILLE UNIVERSITY HOSPITAL AND CENTRE OSCAR LAMBRET A pre-existing collaborative research policy has been built since 1999 between Lille University Hospital and Centre Oscar Lambret. This strong partnership aims at supporting and developing collaborative research projects and networks in the field of oncology. More recently, in 2006, those 2 institutions have created a joint structure named “GCS CRRC” in order to strengthening their research relationship and promote new innovative projects. ONCOLille will rely on this experience and know-how in order to establish a support policy, in close cooperation with the PRES ULNF, the SATT Nord de France Valo and its partner Eurasanté, aiming to boost promising projects towards the best means of IP licensing and dissemination.

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V.2.1.2. THE FRAME OF THE COOPERATION WITH THE SATT NORD DE FRANCE VALO AND EURASANTE Established in January 2009, PRES Université Lille Nord de France was founded by the six public universities in the region Nord-Pas de Calais and two Graduate Engineering school.The PRES Université Lille Nord de France gathers 130,000 students, 4,600 researchers and academics, 3000 PhD in six thematic doctoral schools, seven competitiveness poles, many recognized centers of excellence. In partnership with the CNRS, PRES ULNF has decided to lump together the existing promotion structures in a SATT (Société d‟Accélération de Transfert de Technologie) called “Nord de France Valo”. This new company is being created in association. The SATT will focus on the maturation steps of the technologies sought to be outlicensed and will also act as a tool devoted to commercialize those technologies,and also to negotiate the transfer with the industrial partners. Within the new SATT Nord De France Valo framework, Eurasante will act as a partner of Lille‟s academic institutions in their process of research valorisation. Eurasanté will operate, on behalf of this SATT, as a tool for incubation and support the emergence of public/private collaborative research project. The ONCOLille initiative will benefit from the support ofSATT Nord De France Valo, as well as from Eurasanté, SATT‟s partner for biotechnology and healthcare sector, for the dissemination and exploitation of its results.

V.2.2. KEY STRATEGIC ACTIONS V.2.2.1. TRANSFORM RESEARCH INVESTMENT INTO IP ONCOLille is committed to creating value through IP rights. The SATT Nord De France Valo and Eurasante will encourage the creation of a patent portfolio that will give ONCOLille a technological & market advantage position Indeed, in order to achieve this goal a valorization advisor will be designated by ONCOLille partners to detect and follow new projects through the different steps of valorization.

V.2.2.2. DEVELOPING AN EFFECTIVE PARTNERSHIP STRATEGY WITH INDUSTRY The main goals are to reinforce existing partnerships and to develop new partnerships.  

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Strong collaborations have been already developed and transformed in a steady flow of spin-off and industrial cooperations: ImaBiotech was founded in 2008 after more than 10 years of research initiated by both Pr Salzet and Pr. Isabelle Fournier in the molecular imaging laboratory (Laboratoire de Spectrométrie de Masse Fondamentale & Appliquée – EA4550 – Université Lille 1 Sciences et Technologies). ImaBiotech has developed a platform integrating complementary imaging, proteomics, and transcriptomics techniques and offers new molecular imaging technologies to pharmaceutical & diagnostics companies primarily.


APPLICATION FILE





Professor Bruno QUESNEL and Doctor Xavier THURU have both initiated the project TuDOR BIOTECH, which will be primarily a contract research organisation specialized in preclinical evaluation of novel anti-tumor agents (Leukemia, immunoescape). The start-up will also conduct internal R&D based on a strong collaboration with Professor B. Quesnel in the field of tumor dormancy, thus focusing on the development of new models and the discovery of drug response markers and of novel therapeutic agents. A strong R&D project is on going with Accuray, the society responsible for the development of the CyberKnife (research contract in 4D evaluation in liver irradiation). Strong partnerships with pharmaceuticals companies in the field of clinical research

Eurasanté will boost interactions between ONCOLille and economic players aiming at fostering collaborative R&D&I projects. Public/Private R&D projects can be backed by different public grant schemes such as 7th Framework Program grants from the UE, IMI (Innovative Medicines Initiative) from the European Federation of Pharmaceutical Industries Associations and the European Commission, such as also France‟s tenders for academia/industry collaborations (FUI projects, Oseo ISI, ANR programs…). Eurasanté will assist ONCOLille teams in setting up such grants. Several topics contained in ONCOLille research program have already generated interest from companies:

Company

148

Description

LUNGINNOV

Development of medical devices for in vitro diagnosis and innovative products to evaluate the endothelial cell dysfunction-associated diseases. The firsts markets are the sepsis and the cancer.

ISOLIFE

Isolife distributes every day isotopes for nuclear medicine purposes. This activity requires a performing network to allow rapid deliveries all over the country. Daily, 70 persons, trained and equipped following ADR regulations, are involved with the distribution.

ONCOVET

ONCOVET is a private veterinary referral center located in Villeneuve d‟Ascq (Nord, France) dedicated to diagnostic, imaging and treatment of spontaneous cancer in dogs and cats. Oncovet has 11 years experience of these specialized activities and is working with a regional international network of over 1000 veterinary practionners in France and in the Benelux countries. The team consists in 10 clinicians and several nurses offering surgical and cancer treatment facilities. Most of Oncovet clinicians had an academic clinical or teaching experience before entering the group and have complementary university diploma in their domain. Oncovet has been working with different pharmaceutical companies and academic laboratories for clinical or preclinical research in the field of oncology for several years.

OCR

The veterinary cancer research center OCR (Oncovet Clinical Research) develops an innovative activity of clinical research on pets (dogs and cats) affected by various spontaneously occurring cancers. OCR is a private


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Company

Description Contract Research Organization that proposes validated animal models of spontaneous diseases. The private-owned dog can stand for a relevant model for various cancers: non-hodgkin‟s lymphoma, mammary tumors, urogenital tumors, bone & soft tissue sarcomas, melanomas, head & neck carcinomas. Founded in 2010, OCR is a start-up with the “Jeune Entreprise Innovante” Label and employs 8 qualified experts including 2 PhDs. OCR is specialized in the design, organisation, monitoring and reporting of GCP clinical studies on animals. OCR has internal R&D programs focused on the validation of animal models. Internal laboratory capacities are available: histology, immunohistochemistry (IHC) managed by a certified pathologist. For oncology projects, tumours are collected, analysed and stored in a tissue bank to later identified specific targets of interest. A PhD project, in collaboration with IRCL (INSERM 837) started in January 2012 on tumor dormancy.

Maco Pharma

MacoPharma has more than 30 years of innovation in global healthcare, with expertise in the field of the main leaders in transfusion therapies, with major innovations contributing to all Stages of Blood Processing.

Innobiochips

Innobiochips provides research to professionals and clinicians with tailormade solutions in microarray technologies, constant back-up, reliable support and expert advice, whatever the scope of the project.

Intestinal Biotech Development

Intestinal Biotech Development is a research service provider with in vitro and in vivo models investigating in the field of digestive inflammation and pain like in Inflammatory Bowel Diseases. It develops preclinical studies for Pharmaceutical, Food Ingredients, and Veterinary companies assessing anti-inflammatory, analgesic properties, metabolic activities of molecules, prebiotics or prebiotics, on the digestive tract.

AQUILAB

AQUILAB is a company active in the field of the new Healthcare technologies. AQUILAB was created in 2000 and focuses on the development and the marketing of software solutions in Radiology and Oncology.

LUNGINNOV

Development of medical devices for in vitro diagnosis and innovative products to evaluate the endothelial cell dysfunction-associated diseases. The firsts markets are the sepsis and the cancer.

ISOLIFE

Isolife distributes every day isotopes for nuclear medicine purposes. This activity requires a performing network to allow rapid deliveries all over the country. Daily, 70 persons, trained and equipped following ADR regulations, are involved with the distribution.

These companies have expressed their interest and intention of collaboration in letters enclosed in appendices.

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V.2.2.3. DEVELOPING A COMMUNICATION AND DISSEMINATION STRATEGY THAT WILL ENHANCE ONCOLILLE ATTRACTIVENESS AND PROFILE: ONCOLILLE AS A LEADING EUROPEAN ONCOLOGY RESEARCH INSTITUTE The communication strategy to be developed by the ONCOLille will need to meet two main objectives: 

Building up the credibility of the ONCOLille: having a specific communication strategy for the organisation will strengthen its credibility in the eyes of the targeted players i at: businesses, researchers, other institutes … Different tools will be used in order to disseminate ONCOLille existence and results such as identity chart ad portfolio, dedicated website, publications, participation and/or organisation of events. The visibility given to ONCOLille will then attract new partners for collaborative research; and foster the participation CARE-IBD project of relevant national and international experts in.



Ensure a continuous dialogue between all oncology players: In order to address the needs and problems faced by the oncology sector, the communication strategy needs to aim at building strong dialogue between all the parties involved in the oncology sector, businesses and researchers.

V.2.3. LINKS WITH TECHNOLOGY TRANSFER STRUCTURES (SATT) Established in January 2009, PRES Université Lille Nord de France was founded by the six public universities in the region Nord-Pas de Calais and two Graduate Engineering schools. It now includes 30 entities, with: Lille University of Science and Technology (Lille 1), Lille 2 University of Health and Law, Lille University Charles de Gaulle for humanities, social sciences, literature and arts (Lille 3), Multidisciplinary Artois University, Multidisciplinary University of the Littoral Opal Coast, Multidisciplinary University of Valenciennes and Hainaut-Cambresis., Ecole centrale de Lille, École des Mines de Douai, CHRU Lille university hospital, Oscar Lambret Center, Insitut Pasteur de Lille and many others. The PRES Université Lille Nord de France gathers 130,000 students, 4,600 researchers and academics, 3000 PhD in six thematic doctoral schools, seven competitiveness poles, many recognized centers of excellence. Its missions are:  

Providing the full range of disciplinary areas, training and research Structuring the relationship between university projects and policies of local governments.

PRES ULNF has decided to lump together the existing promotion structures in a SATT (Société d‟Accélération de Transfert de Technologie) called “Nord de France Valo”. This new company is being created in association with University of Picardie Jules Verne (UPJV, Amiens), University Reims Champagne Ardennes (URCA, Reims) and CNRS. The SATT will focus on the maturation steps of the technologies sought to be out licensed and will also act as a tool devoted to commercialize those technologies, devoted also to negotiate the transfer with the industrial partners. Within the new SATT framework, Eurasanté will act as a partner of Lille‟s academic institutions in their process of research valorisation. Eurasanté will act, on behalf of this SATT, as a tool for incubation and a tool accompanying the emergence of public/private collaborative research projects. The SIRIC initiative will benefit from the support of this SATT, as well as from

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Eurasanté, SATT‟s partner for biotechnology and healthcare sector, for the dissemination and exploitation of its results.

V.2.4. LINKS WITH COMPETITIVENESS CLUSTERS In the Nord-Pas de Calais region, as in other areas of Europe, the challenge of effectively transferring knowledge toward the industrial sector and the wider society is a major one. It is addressed by various instruments of which the most recent has been the constitution of pôles de competitivité (competitiveness clusters). The Nord-Pas de Calais Area contains seven such nationally recognised clusters involving research teams from the region. The Nutrition Health and Longevity (NHL) competitiveness cluster gathers, in the Lille area, 80 companies and research institutes in the fields of both nutrition and therapeutic. This NHL cluster is managed by Eurasanté, a non-profit agency dedicated to economic development for biotechnology & healthcare in Lille / Nord-Pas de Calais. Eurasanté is also managing an incubator specialized in the biotechnology and healthcare sector as well as a science park located at the outskirts of Lille‟s University Hospital Site.

Deliverables:     

M6 Frame of the cooperation defined between ONCOLille and SATT/Eruasanté M12 Promotion and valorization plan approved by ONCOLille M18 Funds on European projects granted to ONCOLille M36 M60 Patenting of one patent per year M 48 M60 Licensing of one patent per year

Planning: 2012 MONTHS

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Partnership and valorisation strategy Frame of the cooperation defined between ONCOLille and SATT/Eurasanté

Funds on European projects granted to ONCOLille

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Licence

Licence

Promotion and valorization plan approved by ONCOLille

MONTHS

Patent

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VI.

Knowledge and practices dissemination program

VI.1.

Spreading excellence, dissemination knowledge

Communication and results dissemination are essential for a successful achievement of the project objectives, to protect participant interests and exploitation perspectives as well as to ensure maximum benefits for the scientific community and the patients. Such activities aim at generating an effective flow of information and communication about the objectives targeted, the results obtained during project progress, the contributions made to knowledge and practices. ONCOLille aims to generate numerous outputs, which are expected to be re-used by different means. An adequate communication and dissemination policy has to be defined and agreed by the consortium. Such a policy will be based on the following assumptions:  

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Communication: basic part of dissemination, consisting in raising awareness on the project‟s aim and objectives, and helping the project to build its identity and profile Dissemination: widespread publication awareness or extensive promulgation of knowledge and information generated within the project. 2 types of dissemination are generally envisaged: - dissemination for Understanding (targeting groups and bringing them new knowledge directly, through conferences and main domain events, publications in scientific journals) - Dissemination for Actions (helping target groups to change practices, through participation to workshops, training activities)


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Figure 1 : A strategic dissemination plan will be established by the WP X leader, through the following methodology

1

What do we want to disseminate?

Shared vision and common understanding of what can be disseminated: 1. description of the project 2. knowledge

2

Who are the stakeholders and what are we offering them?

Identification of target audience or groups: 1. internal (employees, managers, supervisory boards, heads of institutions) 2. external (scientific community, citizens) 3. connected (users, other funded projects) Identification for each of them of the issues the project will help to overcome

3

When do we disseminate?

Based on project work plan identifying deliverables and milestones Trying to maintain activities all along project progress (allowing partners being actively engaged and mobilised through ownership feeling)

4

What are the most effective ways to disseminate?

Match vehicles for dissemination with objectives Adopt a multi-strand approach to ensure effectiveness of efforts. Explore and evaluate all available & relevant methods: emailing, newsletter, reports, website, briefings, workshops, road shows, conferences, one-to-one, media

5

Who might help us disseminate?

6

How much does it cost?

Ensure that dissemination activities have been carefully costed once they have been broken down (avoid surprises)

7

How do we evaluate the success?

Put in place suitable mechanisms for reviewing progress and the extent to which the strategy is meeting our objectives

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Work through existing channels (more profitable than creating further tools) that would overload them


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VI.2.

Dissemination to the professionals

Organization of knowledge dissemination is already structured between principally the universities and the CHRU and COL. Additional action will be developed in the framework of ONCOLille and the program will be headed by Dr. Sophie Fantoni (CHRU).

VI.2.1. EXISTING DISSEMINATION PROGRAMS VI.2.1.1. ACADEMIC TEACHING An integrated education and training program is currently being developed. Indeed, many courses (DU and DIU) are organized within our institutions (for example, Lille 2 university organizes: DU Psycho-oncology, DIU Neuro-Oncology, DIU Onco-Urology, DIU Interventional Radiology in Oncology, DIU External radiotherapy of high technicality). These meetings are the ideal place for the dissemination of ONCOLille‟s research results. A partnership with SIRIC‟s researchers will be made to encourage the rapid transmission of data from ONCOLille programs to young doctors in training. A Master degree « Research Biology and Health » organized jointly by Lille1 and Lille2 universities and associating CHRU, COL and research establishments aims to make the future clinicians aware of medical research but also to train young scientists to research. Scientific advances will be disseminated to the young practitioners in the framework of this master. As presented in the project, there is strong interaction with main Universities through all the graduate and post graduate education programs. LMD programs are ongoing with specific actions in the PhD field with grants from the Universities, the Regional Council and the Ministry of Research (Contracts CIFRE).

VI.2.1.2. PROFESSIONAL TRAINING There is already a wide range of existing training and education in the oncology field. For example the Oscar Lambret Centre developed an Education and Training Institute in 2008 (Institut de formation Oscar Lambret). In 2009 and 2010 more than 600 postgraduate students attended over 40 specialised events (42 in 2010) with 32 teachers (Radiotherapy days, palliative care, PEC Head and Neck, PEC breast, aging, surgery, ...). The majority of participants are from the inter-regional area (92 %) and most are from private or general hospitals. Strong links already exist with the outpatients networks (Santelys….). ONCOLille research results could be disseminated during these courses particularly in sessions concerning pathologies addressed in scientific programs 1 and 2 and the new practices resulting from ONCOLille‟s work will be incorporated. Specific post graduate training workshops are also developed for physicians as the “radiotherapy days” in January, bringing more than 150 radiation oncologists, physicists and technician from the region and more largely from France, Spain and North Africa, or the “surgical workshops” with “live” demonstration in the fields of gynecological and breast oncology . Training sessions are organized on an international level. For example with Accuray (CyberKnife Company) for which the COL is training Centre for European and Middle East new users.

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VI.2.2. TOOLS TO BE IMPLEMENTED VI.2.2.1. DEVELOPMENT OF MASTER DEGREES Along already existing masters (for example: Master in Social Law, Master in Clinical and Social Health Psychology), new actions may benefit from ONCOLille : the development of a master in medical physics, an e learning program for the pharmacists around the new molecules in oncology, a master in oncology nursing and a master in therapeutic education. 1. Master in medical physics: The Master in medical physics started in September 2010 and has been ranked A in the preliminary evaluation of its program by the Agence d‟Evaluation de la Recherche et de l‟Enseignement Supérieur (AERES). 2. Master in oncology clinical research and nursing Oncology nurses are facing new challenges. The role played by clinical research and the inclusion of patients in trials mean that trained “clinical research nurses” are needed. Improvements in care and increased life expectancy for most of our patients bring with them new questions around training and adaptation of the work to a situation where more patients are living for longer and expressing new needs and potential new morbidities. ONCOLille will provide information on follow-up of patients and will support this specific training (organised within the framework of the Lille Health Engineering Institute (Institut Lillois d‟ingénierie de la Santé – ILIS, University Lille 2I), in collaboration with the nursing schools (masters degree)). 3. Master in therapeutic education (Care and autonomy in chronic diseases) University Lille 1, Lille 2, Lille 3, CARSAT Nord Pas de Calais Picardie ONCOLille will support therapeutic education through the development of a master's degree in coaching and educational therapy in Lille (the university diploma in Patient Education (DUEP) created in 1998), that will strengthen the training of instructors and program coordinators. The objective of this diploma is to enable health professionals to coordinate integrated therapeutic education in the context of adapted care for chronic disease management.

VI.2.2.2. DEDICATED WEB PAGE 1. Web Page For the dissemination of knowledge and practices, ONCOLille will create its website with a system of subscription to a monthly newsletter to better target professionals concerned with scientific projects. These tools allow professional to keep regularly informed about ONCOLille direction and results. 2. E-learning In 2010, C2RC made the strategic decision to set up an e-learning program dedicated to training and information. One of the pilot initiatives at Centre Oscar Lambret is aimed at the pharmacists. Modern medical oncology treatments are based increasingly on oral drugs (targeted therapies). Such new compounds are radically changing patient care, entailing new training needs for professionals outside the hospital setting. There are already specific training activities for nurses and doctors, but few have been organised for pharmacists. E-learning is one of the possible tools available to bring the information directly to the pharmacy and to achieve the best response if necessary. Based on strong collaboration between the hospitals and

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universities, this program coordinated by Prof. JL Cazin should start in 2011 and will be evaluated over the following years. The aim is to transform the SIRIC recommendations (Program 3) into a strong “e decision making process” at the patient‟s bedside.

VI.2.2.3. ONCOLILLE SCIENTIFIC SEMINARS The steering committee will organize, one a year, a day of cancer, a scientific meeting about oncology dedicated to the regional professionals, doctors, researchers and students and industrials implicated in the project. The seminar will be also open to patient associations with particular sessions iwhere ONCOLille advance and results will be popularize and explained to the patients. The objective is to gather all the players of Tonco Lille and to assess progress made on the ONCOLille research. To complete this meeting, special workshops, more focused will be organized in relation with axes developed in the scientific programs and it will be the place for exchanges between scientific researchers, clinicians and HSS researchers.

VI.3.

Dissemination to the patients and the public

VI.3.1. ACTION OF THE REGIONAL COUNCIL “THE WEEK AGAINST THE CANCER” Because cancer is a leading cause of premature death in our region, it is crucial for the public not to ignore any solution to better inform, help and support the patients and their families. For the last 5th consecutive years, the Regional Council and its partners organized a "Cancer Week" from 15 to 22 November 2011. The week of mobilization is organized in articulation with the National League against cancer and the “regional plan against cancer”. The Region Nord-Pas de Calais is committed, alongside the State, in this regional plan against cancer. This week of mobilization is one of the key actions of this regional plan directed towards patients. Research in medicine, in the causes of cancers (including alcohol, tobacco), in the factors which may protect against cancers, in screening reinforcement and patients and family care have been the themes of the week. This event, unique in France across a whole region, had in 2011 animations in 28 cities of the region with general public animation, shows and public lectures and discussions and cancer news on local radios. (http://www.semainecancernordpasdecalais.org/programme2011). ONCOLille, according to the main goals of this week, will be a stakeholder of the demonstration in reinforcing research on priority cancers of the region, in strengthening the observation on cancer as tools for decision, in disseminating principal results to professional and public and in acting on individual and collective determinants and favour the cancer screening.

VI.3.2. COMMUNICATION TO THE PATIENTS Since 2006, the CHRU along with a number of partners, in particular the Regional Council of Nord-Pas de Calais has created a telephone desk for responding and assisting patients. It is implanted in the occupational medicine and professional pathologies department: "SantéEmploi-Info-Services" (SEIS= Health-Employment-Information-Services). This has started from the complete unawareness of patients of the numerous existing systems and the necessity of developing large proximity assistance (regardless of place of residence in the region). This is an innovating regional action with direct links to regional partners with the goal of avoiding socioprofessional marginalisation of people who had cancer treatment, by facilitating access to

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information and by answering legal and/or medical-social-professional questions asked by family and friends. In terms of operational aspects, this involves orienting people with health and employment problems to professionals of health and of job preservation/reinsertion, to organize personalised relations between the professional and the demander and medium-term follow-up of people benefiting from this service by trained nurses. SIRIC will be an efficient tool to support of this platform, to develop associated research programs and to conduct actions for the reinforcement of post-treatment follow-up of patients and favouring the return to work. Deliverables      

M6: Dissemination Strategic Plan approved M6: WebSite implemented M12: First E learning course for pharmacists implemented M21: First promotion qualified Master in oncology research and nursing M21: First Promotion qualified master in therapeutic education M12 - M60: ONCOLille seminar organized (one yearly)

Planning 2012 MONTHS

1

2

3

4

5

6

7

2013 8

2014

2015

2016

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Knowledge and practices dissemination Dissemination Strategic Plan approved

E learning course for pharmacists implemented

2

3

4

5

6

7

2012

157

8

ONCOLille Seminar

First promotion qualified Master in oncology research and nursing

ONCOLille Seminar 1

ONCOLille Seminar

ONCOLille Seminar First promotion qualified Master in therapeutic education

Website implemented

MONTHS

ONCOLille Seminar

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2013


2014

2015

2016

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