Combating Resistance to Antiangiogenic Therapy in Renal Cell Carcinoma

 描述(申请人提供)：在转移性肾细胞癌(RCC)患者中，用酪氨酸激酶抑制剂(TKI)阻断血管内皮生长因子受体(VEGFR)治疗在许多情况下会导致肿瘤反应，但治疗耐药性是不可避免的。抗血管生成治疗领域的两个基本问题是：肿瘤如何在血管内皮生长因子途径被阻断的情况下重新获得血液供应，以及如何改进目前对肾癌患者的抗血管生成治疗。这项建议旨在改进目前的抗血管生成治疗策略，并确定使用体内模型系统和患者样本早期翻译来评估药效学靶点参与的方法。这个项目的假设是，在VEGFR抑制的背景下，血管生成非依赖通路可以支持血管生成，同时抑制血管生成依赖和独立通路可能导致完全的血管生成阻断，从而停止肿瘤的生长。一个耐药的小鼠肾细胞癌模型将被用来研究两个这样的候选通路，SPHK(鞘氨醇激酶)和ALK1(激活素样激酶1)通路。这些通路与血管生成有关，当肿瘤逃脱VEGFR阻滞剂时，这些通路上调。针对这些候选通路的药物在本提案中提出的初步实验中已显示出有效性，基于这些数据，正在开发这些药物在肾癌患者中的临床试验。本项目寻找针对这些通路的改进策略，并研究肾癌患者这些通路的激活情况。这项提案试图回答的一个基本问题是，在对VEGFR TKI治疗产生抵抗时，哪些分子途径与患者相关。这项研究建议获取患者耐药疾病的活检组织，并首次评估是否可以确定耐药途径，为更好地选择后续治疗铺平道路。

 DESCRIPTION (provided by applicant): In patients with metastatic renal cell carcinoma (RCC) blockade of the vascular endothelial growth factor receptor (VEGFR) with tyrosine kinase inhibitor (TKI) therapy leads to tumor response in many cases, however resistance to therapy is inevitable. Two fundamental issues in the field of antiangiogenic therapy are how tumors can recruit a blood supply despite blockade of the VEGF pathway and how to improve current antiangiogenic treatments for patients with RCC. This proposal seeks to improve current antiangiogenic therapeutic strategies as well as identify means of assessing pharmacodynamic target engagement using in vivo model systems and early translation in patient samples. The hypothesis of this project is that VEGF-independent pathways can support angiogenesis in the setting of VEGFR inhibition and that simultaneous inhibition of VEGF-dependent and independent pathways could lead to complete angiogenic blockade causing cessation of tumor growth. A murine RCC model of resistance will be used to study two such candidate pathways, the SPHK (sphingosine kinase) and the ALK1 (activin-like kinase 1) pathways. These pathways have been implicated in angiogenesis and are upregulated when tumors escape VEGFR blockade. Agents that target these candidate pathways have shown efficacy in preliminary experiments presented in this proposal and based on these data, clinical trials of these agents in RCC patients are being developed. This project searches for improved strategies to target these pathways and study the activation of the pathways in patients with RCC. One fundamental question this proposal seeks to answer is what molecular pathways are relevant in patients at the time of resistance to VEGFR TKI treatment. This study proposes to obtain biopsies of resistant disease in patients and, for the first time, assess whether resistance pathways can be identified, paving the way to better selection of subsequent therapies.