Combating Resistance to Antiangiogenic Therapy in Renal Cell Carcinoma

 描述（由申请方提供）：在转移性肾细胞癌（RCC）患者中，使用酪氨酸激酶抑制剂（TKI）阻断血管内皮生长因子受体（VEGFR）治疗在许多情况下导致肿瘤缓解，但对治疗的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，尽管VEGF通路被阻断，但肿瘤如何招募血液供应，以及如何改善目前RCC患者的抗血管生成治疗。该提案旨在改善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中的早期翻译评估药效学靶点参与的方法。该项目的假设是，VEGF非依赖性途径可以在VEGFR抑制的情况下支持血管生成，并且VEGF依赖性和非依赖性途径的同时抑制可以导致完全的血管生成阻断，从而导致肿瘤生长停止。将使用小鼠RCC抗性模型来研究两种这样的候选途径，SPHK（鞘氨醇激酶）和ALK 1（激活素样激酶1）途径。这些途径与血管生成有关，并且当肿瘤逃避VEGFR阻断时上调。靶向这些候选途径的药物在本提案中提出的初步实验中显示出疗效，并且基于这些数据，正在开发这些药物在RCC患者中的临床试验。该项目寻找针对这些通路的改进策略，并研究RCC患者中通路的激活。该提案试图回答的一个基本问题是，在VEGFR TKI治疗耐药时，哪些分子途径与患者相关。这项研究旨在获得患者耐药疾病的活检，并首次评估是否可以识别耐药途径，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.