A comprehensive pharmacogenetic study of sorafenib in renal cell carcinoma patien

描述（由申请人提供）：本申请的总体目标是首次确定索拉非尼疗效和副作用的遗传标记（BAY 43-9006）。索拉非尼拮抗VEGF受体酪氨酸激酶和Raf激酶，以及许多其他信号分子。肾癌动物模型的体内数据表明，索拉非尼对肿瘤生长的抑制、肿瘤停滞或稳定与肿瘤血管生成的减少密切相关。由于索拉非尼对促血管生成因子的抑制作用在其抗肿瘤活性中具有突出作用，而促血管生成因子在RCC中具有失调的活性，我们假设，编码VEGF及其下游效应物以及其他索拉非尼靶点的基因的种系变异可能与索拉非尼在RCC患者中的疗效差异有关。我们还假设种系遗传变异可能与索拉非尼治疗患者常见副作用的发生有关。先前参加TARGET索拉非尼研究的337例晚期RCC患者将对50个索拉非尼药理学候选基因中的1200个单核苷酸多态性进行基因分型，这表明索拉非尼是一种非常有效的治疗这种疾病的药物，并于2005年获得FDA批准。由于索拉非尼治疗的RCC患者的生存期相对较短，以及短期毒性对剂量和治疗持续的负面影响，鉴定索拉非尼结局的遗传标记具有最高的科学和临床价值。这种分析以前从未进行过，并且有望实现晚期RCC患者的个体化治疗。公共卫生相关性：这是一项TARGET研究中337例接受索拉非尼治疗的肾细胞癌患者的药物遗传学研究。该提案的总体目标是首次确定索拉非尼疗效和副作用的遗传标记。

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.