Genetic Predictors of Response to mTOR inhibitors in advanced Renal Cancer

描述（由申请人提供）：雷帕霉素（mTOR）抑制剂（替西罗莫司或依维莫司）的机制靶标是晚期肾细胞癌（RCC）的标准选择。尽管与3期注册试验（IFN-γ或安慰剂）的对照组相比，这些药物具有明显的临床益处，但这些药物价格昂贵，可能具有显著的毒性 最重要的是，反应通常是短暂的。目前，在转移性肾细胞癌中没有临床上有用的预测对靶向治疗的反应或抵抗的生物标志物。一些证据表明，治疗结果可能由个体肿瘤中激活的特定遗传改变和信号通路决定。在对来自对替西罗莫司有反应的RCC患者的11个肿瘤的初步实验中，我们注意到11个反应者中的6个（55%）在1个或多个mTOR通路基因中具有变异。与之相比，在肾细胞癌人群中有约15-20%的mTOR途径突变。我们的第一个目标是通过对所有RCC和mTOR通路基因进行靶向测序，确定RCC中对靶向mTOR通路的药物反应的遗传预测因子。我们的第二个目标是使用匹配的进展前和进展后样本的全外显子组测序，鉴定在最初对mTOR抑制剂有反应然后进展的肿瘤中发生的获得性突变。我们的长期目标是对mTOR通路突变与RCC中雷帕霉素类似物的临床益处相关的假设进行明确的检验。就公共卫生意义而言，我们的工作应该使我们能够确定那些最有可能受益于mTOR抑制剂的患者，并能够了解对这些疗法的耐药机制;因此，我们将通过开发个体化治疗方法来改善晚期RCC患者的生存和生活质量。我们的项目很可能在短时间内转化为临床应用，并与肾脏领域有重大关系 癌症是一种每年导致超过13，000名美国人死亡的疾病。

DESCRIPTION (provided by applicant): The mechanistic Target of Rapamycin (mTOR) inhibitors (temsirolimus or everolimus) are standard options in advanced renal cell cancer (RCC). Despite the obvious clinical benefit compared to the control arms from the phase 3 registration trials (IFN-� or placebo), these drugs are expensive, can carry significant toxicities and most important, responses are usually short-lived. At present, there are no clinically useful predictive biomarkers of response or resistance to targeted therapy in metastatic RCC. Several lines of evidence suggest that treatment outcome is likely to be determined by particular genetic alterations and signaling pathways activated in individual tumors. In a preliminary experiment on 11 tumors from RCC patients who responded to temsirolimus, we noted that 6 of the 11 (55%) responders had a variant in 1 or more mTOR pathway genes. This compares to a background of ~15-20% mTOR pathway mutations in an unselected RCC population. Our first aim is to identify genetic predictors of response to agents targeting the mTOR pathway in RCC using targeted sequencing of all RCC and mTOR pathway genes. Our second aim is to identify acquired mutations that develop in tumors that initially respond to mTOR inhibitors and then progress, using whole exome sequencing of matched pre and post-progression samples. Our long term objective is to perform a definitive test of the hypothesis that mTOR pathway mutations are associated with clinical benefit to rapalogues in RCC. In term of public health significance, our work should allow us to identify those patients with the highest chance of benefit to mTOR inhibitors, and enable an understanding of mechanisms of resistance to these therapies; thereby we will improve both the survival and quality of life of patients with advanced RCC by developing an individualized therapeutic approach. Our project is likely to translate into clinical application within a short period of time and be of major relevance to the field of kidney cancer, a disease that results in more than 13,000 US deaths annually.