A comprehensive pharmacogenetic study of sorafenib in renal cell carcinoma patien

描述（由申请人提供）：本提案的总体目标是首次确定索拉非尼（BAY 43-9006）疗效和副作用的遗传标记。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。肾癌动物模型中的体内数据表明，索拉非尼观察到的肿瘤生长抑制和肿瘤停滞或稳定与肿瘤血管生成减少密切相关。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，因此我们假设编码VEGF及其下游效应物以及编码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患者中的疗效差异相关。我们还假设生殖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。索拉非尼药理学的50个候选基因中的约1200个单核苷酸多态性将在先前参加TARGET索拉非尼研究的337名晚期RCC患者中进行基因分型，该研究已经证明索拉非尼是这种疾病的高效治疗，导致其FDA于2005年批准。由于接受索拉非尼治疗的RCC患者的生存期相对较短，以及短期毒性对给药和继续治疗的负面影响，因此索拉非尼结局的遗传标记的鉴定具有最高的科学和临床价值。这种分析以前从未进行过，并有望实现晚期RCC患者治疗的个体化。公共卫生相关性：这是一项在TARGET研究中对337例接受索拉非尼治疗的肾细胞癌患者进行的药物遗传学研究。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.