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In recent years, we have become involved in clinical research by taking part in studies involving immunotherapy, and then angiogenesis (sunitinib, sorafenib, everolimus) and to elucidate the toxicities induced by these drugs in renal cancer. We have also established a standard chemotherapy treatment for Bellini duct tumors (1-2% of renal cancers), and we are working on unusual kidney tumors (type 1 and 2 papillary tumors, which are chromophobic and sarcomatoid). Our research project is intended to elucidate the mechanisms underlying resistance or sensitivity towards the drugs used to treat renal tumors.

Research project "Genomics of kidney tumors: from identifying new carcinogenesis pathways to clinical applications"
The research projects that have been undertaken follow on from clinical results showing that these antiangiogenics have a major activity in kidney cancer. Our team has contributed to the clinical positioning of these drugs in kidney cancer (Sutent® first line, Nexavar® second line, everolimus second or third line), and has also identified renal (Frangié et al, Lancet Oncology, 2007), cardiovascular (Azizi et al, NEJM 2008), cerebral (Medioni et al, Target Oncol 2007) and systemic (Bhojani et al, Eur Urol, 2008) toxic effects. An assessment of the resistance mechanisms and toxicities induced by these treatments will be explored in a way that leads both to translational topics for clinical application, and more fundamental topics.

Genetic and transcriptomic changes and renal clear cell carcinomas.
Background of the first study: The objective of this study, based on a multicenter retrospective national survey of frozen renal tumors from patients treated with anti-angiogenics for metastatic kidney cancer is to define a molecular signature to predict how the tumor will respond to anti-angiogenics. The tumor specimens have been kept in accordance with the standard stipulated by the [French] Centres de Ressource Biologiques. This multicenter study involves more than 20 centers in France (consisting of a triad of oncologists, urologists and pathologists at each center). These centers are involved in the treatment of metastatic kidney cancer, and in international studies of anti-angiogenic treatments (Phase III Pfizer: Sunitinib first line; Phase III Bayer: Sorafenib second and first lines; phase III Roche: Bevacizumab + interferon first line).
Description of the tumors collected: The CIT call for tenders resulted in a collaboration involving about twenty centers, providing this project with a total of 254 tumors that had been frozen under excellent conditions and could be used immediately. This tumor archive at a national scale involved the joint participation of teams of urologists, oncologists and pathologists, thus facilitating future collaborative projects, for adjuvant and neoadjuvant strategies. All the tumors will be frozen at -80°C, in either isopentane or liquid nitrogen.
Qualification of the specimens: We anticipate a failure rate of about 10% in extracting the nucleic acids from the tumors. This failure rate has been estimated on the basis of analyses already carried out on the same collection of tumors. Out of the 254 tumors, we therefore expect about 230 RNAs of sufficiently good quality to permit hybridization on a chip. All the tumors will be extracted using Qiagen kits. For all the tumors, one fragment will be kept for the protein studies, and some slides kept for immunohistochemistry studies.
For each specimen, a clinical-and--pathological results report form will be completed by the source team, specifying the histological characteristics (clear cell carcinoma or other histological type) of the fragment, and the patient's clinical data (type of surgery, previous treatments, type of response to treatments, Motzer and other prognostic factors …). The patients may have received different types of treatment before their anti-angiogenic treatment (immunotherapy, chemotherapy, surgery …), and this information will be clearly recorded so that it can be analyzed. The different types of response depending on the previous treatments will be assessed, and taken into account in the analysis of the factors governing the response to anti-angiogenics
Experimental aspect: It is intended to select an initial series of 127 tumors for Affymetrix hybridization and CGH array on the LNCC platform. All the tumors will be accompanied by their clinical and pathology information, and the tumors we will include at this stage will consist of about 35% of tumors showing a partial response, 40% displaying tumor stabilization and 25% that have progressed, i.e. that have not responded to the treatment. These tumors will be characterized with regard to several candidate genes known to be involved in the response to anti-angiogenics: The mutations of the VHL gene will be looked for by direct sequencing of the whole coding sequence. The results will be interpreted on the basis of the predicted functional consequences of the mutations (substitution or truncating mutations), and on the basis of the level of expression of the messenger RNA of VHL to detect extinctions of expression that could be secondary to methylation events. Alongside this, we will measure the expression of the different messenger RNAs transcribed by the target genes of VHL and/or the anti-angiogenics. Thus we intend to analyze VEGF and its receptors, HIF and PDGF. Finally, the P53 pathway will also be systematically explored by looking for P53 mutations and P16/P14ARF deletions, which have been identified in about 20% of cases of renal clear cell carcinomas. In view of the complex nature of the changes in the P53 pathways in renal carcinomas, the RNA of P53 and P14 will also be determined by quantitative PCR.
The results of the transcriptome and CGH-array studies will be analyzed on the basis of the response to treatment and correlations with the changes in candidate genes will also be looked for. As the first step, the response to antiangiogenic treatment will be assessed for all three randomized protocols taken together. This strategy is justified by the fact that sunitinib, sorafenib and bevacizumab all have the same targets. We will then move on to looking at the potentially specific effects of each drug. In our analysis, we will also try to identify the effects of the different clinical, histological and molecular characteristics of tumors on their response to treatment.
The signatures of genic expression and CGH predictive of 100 to 120 tumors (the exact figure remains to be determined after qualification of the nucleic acids), which have similar clinical, and pathological and treatment characteristics that can be compared using the quantitative PCR platform.
Second study: This prospective study is based on a clinical, radiological, vascular, biological and molecular evaluation of using an anti-angiogenic, sunitinib, BEFORE and AFTER nephrectomy in patients with metastatic kidney cancer ("neoadjuvant" treatment). A histological assessment based on immunohistochemistry and genomics will be carried out on the initial tumor biopsy, of the surgical specimen of the kidney tumor, and of the adjacent healthy kidney tissue (transcriptome and CGH array studies). In addition, biological, immunological and vascular imaging assessments will be carried out in order to establish correlations between the clinical and laboratory findings. This trial involves the participation of 100 patients included at 15 French centers. All the exams will be carried out in all the patients, apart from the analysis of certain markers carried out on fresh blood, which will involve just 60 patients (circulating tumor cells, T-lymphocyte regulators, platelet microparticles, circulating endothelial cells and their precursors).
 
 


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