A comprehensive pharmacogenetic study of sorafenib in renal cell carcinoma patien

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DESCRIPTION (provided by applicant): The overall goal of this proposal is to identify, for the first time, genetic markers of efficacy and side effects of sorafenib (BAY 43-9006). Sorafenib antagonizes VEGF receptor tyrosine kinases and Raf kinase, as well as numerous other signaling molecules. In vivo data in animal models of renal cancer indicate that the observed tumor growth inhibition and tumor stasis or stabilization of sorafenib correlate strongly with decreased tumor angiogenesis. As sorafenib inhibition of pro-angiogenic factors has a prominent role for its antitumor activity and pro-angiogenic factors have a dysregulated activity in RCC, we hypothesize that germline variation of genes coding for VEGF and its downstream effectors, as well coding for other sorafenib targets, might be associated with differences in efficacy of sorafenib in RCC patients. We also hypothesize that germline genetic variation might be associated with the occurrence of common side effects experienced by patients treated with sorafenib. About 1200 single nucleotide polymorphisms in 50 candidate genes of sorafenib pharmacology will be genotyped in 337 advanced RCC patients previously enrolled in the TARGET sorafenib study, which has demonstrated that sorafenib is a highly effective therapy in this disease, leading to its FDA approval in 2005. Due to the relatively short survival of RCC patients treated with sorafenib and the negative impact of short-term toxicities on dosing and continuation of treatment, the identification of genetic markers of sorafenib outcome is of the highest scientific and clinical value. Such analysis has never been conducted before and holds the promise of achieving the individualization of therapy of advanced RCC patients. PUBLIC HEALTH RELEVANCE: This is a pharmacogenetic study in 337 renal cell carcinoma patients treated with sorafenib in the TARGET study. The overall goal of this proposal is to identify, for the first time, genetic markers of efficacy and side effects of sorafenib.