Tumori, 97: 137-141, 2011
Targeted therapy in head and neck cancer Chiara Bianchini1, Andrea Ciorba1, Stefano Pelucchi1, Roberta Piva2, and Antonio Pastore1 1 ENT Department, University Hospital of Ferrara, Ferrara; 2Molecular Biology Section, Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
ABSTRACT
Aims and background. This review focuses on recent advances in understanding the molecular mechanisms at the basis of cancer initiation and progression in the head and neck and also discusses the possible development of targeted cellular strategies. Intrinsic and acquired resistance of cancer cells to current conventional treatments, as well as recurrence, represent a major challenge in treating and curing the most aggressive and metastatic tumors also in the head and neck. Even though in some hematologic malignancies (i.e., non-Hodgkin’s lymphomas) antibodies specifically designed to target tumor-specific cells have already been introduced, in solid tumors molecular targeted therapy is now entering clinical practice. Methods. A PubMed database systematic review. Results and conclusions. Molecular targeting could achieve specific damage to cancer cells, at the same time preserving functionally important tissues. This could offer new prospectives in primary and adjuvant treatment also of head and neck tumors.
Introduction Head and neck cancer is still the sixth most common cancer type worldwide. Surgery, radiotherapy and chemotherapy, alone or in combination, are considered the main therapeutic approaches. Disappointingly, despite significant advances in head and neck treatments, survival rates and prognosis have only improved moderately through the years1. Recently, studies have suggested that several factors may be involved in the head and neck carcinogenetic process. The highly tumorigenic “expression” of some cancer types, cancer progression to locally invasive and metastatic states, and recurrences are often associated with resistance to treatments. This could be explained by accumulating genetic and/or epigenic alterations in cancer cells that may contribute to their uncontrolled growth, survival and invasion, as well as to their intrinsic or acquired resistance to clinical treatments2. In particular, the concept of cancer stem cells or cancer-initiating cells has been proposed to explain cancer initiation and progression to metastatic disease states and resistance to conventional therapies3-5. A major problem in the treatment of cancer is still the specific molecular targeting of neoplastic cells. Ideally, future therapies should act over short distances to minimize damage to healthy cells and target tumor compartments that have the highest sensitivity. In the present review, the importance of considering these new concepts in the role of cancer progenitor cells and cancer development in order to overcome resistance to conventional cancer therapies is discussed.
Cancer stem cells in head and neck tumors There already are several reports that focus on the possible role of stem cells in cancer occurrence and progression in head and neck tumors3,6,7. It is likely that carcino-
Key words: cancer stem cells, cancer treatment, head and neck cancer, targeting therapy. Acknowledgments: The oncologic project of the ENT Clinic and of the Molecular Biology Section at the University of Ferrara is supported by a grant for scientific research from the University of Ferrara. Correspondence to: Chiara Bianchini, MD, ENT Department, University Hospital of Ferrara, C.so Giovecca 203, 44100 Ferrara, Italy. Tel +39-0532-236383; fax +39-0532-237615; e-mail
[email protected] Received May 3, 2010; accepted December 6, 2010.
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genesis should be considered as a multistep process, in which an accumulation of genetic and epigenetic alterations forms the basis for development from a normal cell to a cancer cell6. Particularly, the alteration of two key genes, p53 and p16, seems to be involved in this process8. Cancer stem cells could represent a minor population of tumor cells that possess the stem cell property of self renewal. De-regulation of stem cell self renewal is a likely requirement for the development of cancer3. The presence of these cancer progenitors may partially explain the rapid recurrence as well as the high metastatic rate of the most aggressive tumors after current clinical treatments. Moreover, the reactivation of several developmental signaling cascades [epidermal growth factor (EGF)/EGFR, stem cell factor/KIT, platelet-derived growth factor (PDGF)/PDGFR, sonic hedgehog (SHH/PTCH/GLI transcription factor, and/or Wnt/catenin)] combined with altered DNA repair and mechanisms of multi-drug resistance in cancer progenitor cells may take part and may be considered responsible, at least in part, for their resistance to current clinical therapies2,9.
Possible specific targets in head and neck tumors Recent advances in basic research, particularly genomics and proteomics, have already improved but will probably develop more in the near future our understanding of the molecular processes governing head and neck cancer origin and progression. It has been reported that the simultaneous blockade of several oncogenic cascades activated in cancer progenitor cells during cancer development has been judged essential for improving the current clinical treatments against high-risk metastatic solid tumors, including head and neck cancers2,10-18. Particularly, the molecular targeting of developmental cascades including hedgehog, Wnt/catenin, Notch, EGFR, PDGFR and KIT pathways and/or oncogenic signaling elements (telomerase, Src, ABL, PI3K/Akt, MYC, NF-KB and survivin), which assume a critical function in regulating the selfrenewal, survival and invasion of cancer progenitor cells as well as in drug resistance and disease relapse, has been defined of therapeutic interest2,10-19 (see also Table 1). So far, the two most promising and advanced strategies are the blockage of growth factor-based cellular signaling and interference with angiogenesis-related pathways. One of the most comprehensive investigated candidate is the EGFR family. EGFR is the most prominent candidate for therapeutic targeting due to its more than 90% expression rate in head & neck squamous cell carcinoma and its influence on regulation of proliferation, apoptosis, metastasis, angiogenesis and cell differentia-
C BIANCHINI, A CIORBA, S PELUCCHI ET AL Table 1 - Possible sites of intervention for arresting head and neck cancer cells progression Molecular targets/ possible sites of intervention
Biological mechanism
EGFR in head & neck Arrest G1 phase cell cycle, squamous cell carcinoma stopping cellular proliferation Insulin-like growth factor Inhibition of intracellular 1 receptor, telomerase, signaling MYC, Bcl-2 p53
Inducing apoptosis in specific neoplastic cells
Cox2
Reduction of cellular growth & angiogenesis
References
3,11,38,39,40
41-44
45,46 47
tion9. It has been reported that down-stream signaling or inhibition of EGFR may result in arrest of the G1 phase of the cell cycle, due to induced upregulation/accumulation of the cyclin-dependent kinase inhibitors p27kip1 and/or p21cip1/waf1, and this may stop cancer cell proliferation9. The extracellular part of the EGFR can be inhibited by monoclonal antibodies and the intracellular part by more or less specific tyrosine kinase inhibitors. A clinically tested EGFR inhibitor is cetuximab, a monoclonal antibody with a high affinity to EGFR, and there are already several encouraging reports about the use of the drug in treating head & neck squamous cell carcinomas2,9,10-19. Instead, there only are very few data available about the use of tyrosine kinase inhibitors in head and neck cancer treatment. In particular, it has been shown that tyrosine kinase inhibitors block EGFR downstream signal transduction pathways, inducing an immediate cell cycle arrest, and significantly inhibit angiogenesis by inducing a decrease in angiogenic growth factors9. Gefinitib and erlotinib are the two most advanced drugs available, but their use is still experimental9,20,21. Currently, EGFR inhibitors have been tested as a single agent or in combination with other therapies. As a single agent, there are several reports showing that these molecules are moderately active in patients affected by head and neck squamous cell carcinoma. In some cases, they have provided disease control with a reasonable therapeutic index in patients who are chemotherapy refractory or are deemed unfit for cytotoxic therapy. However, the activity of single-agent antiEGFR therapy in the head and neck squamous cell carcinoma setting is largely based on uncontrolled, singlearm, phase II trials (see also Table 2). Few phase II and III trials have tested the addition of cetumibax to cisplatin in patients who resulted refractory to platinum-based therapy. Nonetheless, so far the combination appears to confer no further benefit over anti-EGFR agents alone (see also Table 2)22,23-30.
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Table 2 - Clinical trials of molecular targeted therapies in recurrent and/or metastatic head & neck squamous cell carcinoma: anti-EGFR molecular-targeted therapies as single agent and in combination (modified from Le Tourneau and Siu22 ) Phase
Reference
Treatment
Overall survival (mo)
Single agent Cetuximab Gefitinib Gefinitib
II II III
23 24 25
Cetuximab 400 mg/day Gefitinib 500 mg/day Gefitinib 250 mg/day
6 5 6
Combination Platinum + cetuximab Platinum + cetuximab Platinum + cetuximab Cisplatin + erlotinib Erlotinib & bevacizumab
II II II II I, II
26 27 28 29 30
Platinum + cetuximab Platinum + cetuximab Platinum + cetuximab Cisplatin + erlotinib Erlotinib & bevacizumab
5 6 4 7 7
Agent
It is known that angiogenesis plays a key role in the pathogenesis of solid tumors, including those of the head and neck. Experimentally, it has already been shown in mice that inhibition of vascular endothelial growth factors and their receptors decreases angiogenesis and tumor growth. Therefore, several strategies to target vascular endothelial growth factors have been developed and are currently being explored. Clinical trials on the use of these types of molecules alone or in combination with conventional chemotherapies are already running17,18. The development of new biological agents should focus on inhibitors that are likely to hit multiple targets. The complexity of aberrant signaling in head and neck tumors explains why interfering with only single steps in this pathway have not yet shown marked clinical responses. Probably, a combination of different agents that target distinct specific pathways is likely to inhibit the escape of tumor cells by alternate mechanisms leading to more effective disease control. Furthermore, different etiological factors and risk habits can result in distinct genetic and epigenetic alterations, which may trigger different signaling pathways, thus impacting differently the development and progression of head and neck tumors. To evaluate the efficacy of these biological agents, there is urgent need to identify novel biomarkers that can be used to accurately assess and individualize therapy31.
The concept of “field cancerization” A genetic progression model of head and neck tumors has to be associated also to the concept of “field cancerization” of the aerodigestive tract. Slaughter et al.32 used the term “field cancerization”, firstly studying 783 patients with oral cancer33. After performing histological examinations, they proposed the concept of field cancerization to describe a situation in which: 1) oral cancer develops in multifocal areas of precancerous change; 2) histologically abnormal tissue surrounds the tumor; 3) oral cancer often consists of multiple inde-
pendent lesions that sometimes coalesce; and 4) the persistence of abnormal tissue after surgery may explain second primary tumors and local recurrences4-6. At the time of the study32, there was no molecular basis for these observations, and the term “field cancerization” has subsequently taken on a slightly different meaning in the literature. In fact, the concept has been re-proposed to explain the development of locally recurrent cancer and/or second primary tumors in head and neck cancer patients by Leemans et al.33, who suggested that head and neck carcinomas recur at the primary site in about 10-30% of the cases with advanced tumors, even when a complete resection of the primary carcinoma has been performed6,34. Ha and Califano35 considered the term of field cancerization from a “molecular” point of view. It could be considered the result of either independent molecular events affecting multiple cells separately, or as a molecular event in a single clonal progenitor that gives rise to the phenomenon. These two mechanisms may not be mutually exclusive and may be simultaneous and/or complementary events35.
Future perspectives Further knowledge, and thus possibly further new therapeutic targets, could arise from the comprehension of head and neck cancer stem cell biology, since methods to isolate and characterize the ex vitro and in vivo properties of cancer stem/progenitor cells have been recently provided and improved. Therefore, a reanalysis of the oncogenic gene products specifically activated in cancer progenitor cells will be necessary. Particularly, further investigations by using cancer stem cells isolated from primary cancer patients’ malignant tissues at different stages during cancer progression and metastatic disease should help to identify new biomarkers for the development of more effective diagnostic and prognostic methods and targeted therapies against aggressive and metastatic cancers.
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However, evaluation of the functional and molecular properties of these cells ex vivo must be considered with caution, since multiple extrinsic factors may influence the in vitro behavior of this subset of cells. More specifically, experimental culture conditions do not necessarily reflect the local tumor microenvironment and the intercellular signaling environment. Further investigations of cancer progenitor cells in more vigorous experimental conditions are required to help to elucidate the molecular mechanisms that provide a critical role for their uncontrolled self-renewal and/or aberrant differentiation capacity. The specific biomarkers and functional properties of cancer progenitor or stem cells clearly should be explored in order to assess selected possible targets. This particularly considering that cancer progenitor/stem cells may also exhibit a differential genomic and proteomic pattern, compared to the bulk mass of further cancer cells11,36-47. It is also necessary to consider that these molecular markers might allow a very sensitive detection of minimal residual cancer cells or micrometastasis in the various body compartments and/or in lymph nodes, thus facilitating the prognosis definition. The development of new effective and safe targeted therapies by eradicating the total population of cancer progenitor cells and their further differentiated progenies at the primary and secondary neoplasms should allow us to improve current cancer treatments, prevent the disease relapse, and thereby induce a complete cytogenetic remission and cure of cancer patients in the clinic. The next few years will be exciting also in terms of surgical technique progresses. A newer pathway of nanotechnology and molecular medicine will also lead to technical advancements in areas such as free tissue transfer, robotics, minimal-access surgery, as well as application of new lasers and optical technologies. Advances in these fields could expand our capabilities to repair, restore and preserve organ/tissue function, thus personalizing and tailoring the treatment to the “individual” patient.
Conclusions A cancer “targeted therapy” actually represents one of the most promising resources in the development of new strategies including in head and neck oncology. A targeted therapy with biological markers in head and neck cancer is a new and fast-growing field with interesting aspects concerning decreasing early and late toxicity with better functional outcome and survival. Since it is likely that carcinogenesis may be considered as a process that arises from the malignant transformation of embryonic or adult stem/progenitor cells into cancer progenitor cells3,6,7, cancer progenitor cells can provide critical functions in cancer initiation and progression into metastatic and recurrent disease states. Based on
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these observations, the molecular targeting of cancer progenitor cells must be considered for improving the efficacy of current cancer therapies. Traditional diagnostic methods such as clinical assessment, histopathological examination and imaging techniques are not considered sufficient to provide all the information related to prognosis and treatment of choice in head and neck cancer36,37. Additional investigations to identify the specific molecular biological characteristics of head and neck tumors should be performed. Only comprehension of the origin and molecular behavior of head and neck cancer will lead us to program and perform a more specific, safe, effective, personalized and targeted therapeutic plan.
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