Poster session 5. Translational research

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Dec 26, 2015 - There is a recent increase in the use of patient-derived tumor xenografts (PDX) engrafted into immunodeficient mice as improved preclinical ...
Annals of Oncology 24 (Supplement 1): i30–i32, 2013 doi:10.1093/annonc/mdt047.7

Poster session 5. Translational research P05:08

SIMILAR PI3K AND RTK-RAS STATUS IN PATIENT DERIVED COLORECTAL CANCER-XENOGRAFTS AND PATIENTS

M. Nunes1, L. B. Weiswald2, P. Vrignaud3, S. Vacher4, E. Turlotte3, S. Richon2, S. Roman-Roman5, I. Bièche4, V. Dangles-Marie5 1 Sanofi, Vitry-sur-Seine, France, 2IFR71, Université Paris Descartes, Paris, France, 3Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Vitry-sur-Seine, France, 4Laboratoire d’Oncogénétique, Institut Curie, St Cloud, France, 5Département de Recherche Translationnelle, Institut Curie, Paris, France

abstracts

© European Society for Medical Oncology 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology and NDDO Education Foundation. All rights reserved.

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There is a recent increase in the use of patient-derived tumor xenografts (PDX) engrafted into immunodeficient mice as improved preclinical models of patient tumors. An important component in the validation of disease-specific PDXs for clinical relevance is comparing the genomic alterations and the response to standard agents. The CReMEC collection of 54 colorectal PDX has been recently reported to mimic the clinical situation for histopathological and molecular diversity of colorectal cancer. We further analyze here this colorectal PDX collection in regard to robust human patient molecular features: 1) Alterations in both PI3K and RTK-Ras

pathways; 2) Role of oncogenic activation of EGFR-Ras downstream signaling on response to cetuximab. The Cancer Genome Atlas Network (TCGA) newly reported a large genome-scale analysis of 276 colorectal cancer tissue samples, showing common genetic alterations in the PI3K and RTK-RAS pathways, with mutual exclusions in the PI3K pathway. The analysis of the PDX panel by CGH array, RNA expression (microarray, real-time qRT-PCR) and exome sequencing confirmed activation with mutual exclusion in PI3K pathway (IGF2 focal amplification/overexpression; IRS2 overexpression, mutation of PIK3CA, PIK3R1 and PTEN homozygous deletion). In RTK-Ras pathway, frequencies of genomic abnormalities (ERBB2 mutation/amplification; mutation of ERBB3, NRAS, KRAS and BRAF) in PDXs are fully in line with the TCGA patient collection. The response to cetuximab of 52 subcutaneous engrafted PDX (including 24 KRAS mutated PDX) has been analyzed according to translated clinical criteria: xenograft regression as been defined as a partial response (decrease of at least 70% of the tumor volume measured at the beginning of the treatment) or as a complete response. In this unselected population, tumor regression occurred in 8 out of 52 cases (15%); all were KRAS wild type tumors. The percentage of responders was enriched up to 30% (7/23) when PTEN deletion and mutations of KRAS, BRAF, and PIK3CA are concomitantly excluded. These results completely fit with recent publication of data in patients treated with anti-EGFR antibodies. Taken together, these results demonstrate that colorectal PDXs are representative clinical colorectal tumor models. They also underline their interest as appropriate tools to identify and test new targeted therapeutics.