Biomarkers for VEGF and mTOR Blockade in Advanced Renal Cancer

描述（由申请人提供）：阻断血管生成和非血管生成途径是一种很有前途的策略，有可能为晚期肾细胞癌（RCC）患者提供显著的益处。为了针对适当的患者进行个体化靶向治疗，有必要识别和验证与临床获益和/或毒性相关的标志物。临床前研究已使我们进入贝伐单抗和CCI- 779的I/II期试验，以确定联合治疗晚期RCC患者的安全性和有效性。我们已经观察到非常令人鼓舞的临床抗肿瘤活性，来自第一组患者的I期部分研究。我们的长期目标是识别和验证可预测临床获益的生物标志物，以及可作为抗血管生成治疗晚期肾细胞癌患者活性和毒性的替代终点的标志物。特异性目的1：鉴定与CCI-779联合贝伐单抗治疗转移性肾细胞癌患者临床获益相关的肿瘤分子标志物。特异性目标2：评估与CCI-779联合贝伐单抗治疗晚期肾细胞癌的反应和毒性相关的循环生物标志物。我们的建议利用了目前对肾细胞癌分子机制的理解和对这种疾病有活性的靶向药物的可用性。本研究产生的数据可能有助于根据肿瘤的分子特征确定将从这种治疗中受益的患者，这是晚期肾细胞癌个体化治疗发展的一步。我们提出的循环生物标志物研究将评估治疗对肿瘤新生血管不同方面的影响，并可能有助于识别抗血管生成治疗有毒性风险的患者。这一信息将对未来在肾癌和其他癌症中使用这些药物的试验设计以及未来的临床实践非常有用。

DESCRIPTION (provided by applicant): Blockade of angiogenic and non-angiogenic pathways is a promising strategy that has the potential to provide significant benefit to patients with advanced renal cell carcinoma (RCC). In order to individualize targeted therapies to the appropriate patients, it is necessary to identify and validate markers correlated with clinical benefit and/or toxicity. Preclinical studies have led us to a phase I/II trial of Bevacizumab and CCI- 779 to determine the safety and efficacy of the combination in patients with advanced RCC. We have observed very encouraging clinical antitumor activity from the first cohort of patients in the phase I portion of the study. Our long term goals are to identify and validate biomarkers predictive of clinical benefit as well as markers that can be used as surrogate endpoints of activity and toxicity in patients with advanced renal cell cancer treated with antiangiogenic therapies. Specific Aim 1: To identify tumor molecular markers associated with clinical benefit to the combination of CCI-779 and Bevacizumab in patients with metastatic renal cell cancer. Specific Aim 2: To evaluate circulating biomarkers associated with response and toxicity to the combination of CCI-779 and Bevacizumab in advanced renal cell cancer. Our proposal takes advantage of the current understanding of the molecular mechanisms of renal cell carcinoma and the availability of targeted agents that are active against this disease. Data generated in this study may help identify patients who will benefit from this treatment based on the molecular features of their tumors, a step forward in the development of individualized treatments for advanced renal cell carcinoma. Our proposed circulating biomarker studies will assess the effects of the treatment on different aspects of tumor neovascularization and may help identify patients at risk for toxicity from antiangiogenic treatments. This information will be extremely useful for the design of future trials using these agents in renal and other cancers and for future clinical practice.