Combating Resistance to Antiangiogenic Therapy in Renal Cell Carcinoma

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 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.