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Combating Resistance to Antiangiogenic Therapy in Renal Cell Carcinoma

对抗肾细胞癌抗血管生成治疗的耐药性

基本信息

批准号：
9114536
负责人：
RUPAL S BHATT
金额：
$ 39.8万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114536
关键词：
ACVRL1 gene Activins Affect Angiogenesis Inhibitors Antibodies BMP10 gene Binding Biochemical Biological Assay Biological Models Biopsy Blood flow Clinical Clinical Trials Data Disease Resistance Endoglin Endothelial Cells Endothelial Growth Factors Receptor Endothelium Enzymes Event Future Genetic Goals Health Lead Ligands Measures Mediating Metastatic Renal Cell Cancer Modeling Molecular Mus Mutate Pathway interactions Patient Monitoring Patients Pharmacodynamics Phase II Clinical Trials Phosphorylation Phosphotransferases Physiological Plasma Production Receptor Inhibition Recruitment Activity Renal Cell Carcinoma Resistance Role Sampling Specimen Sphingosine Sphingosine-1-Phosphate Receptor Testing Therapeutic Time Translating Translations Tumor Escape Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factors Vascular blood supply Xenograft Model angiogenesis antitumor effect base bone morphogenetic protein 9 combat density design extracellular improved in vivo in vivo Model inhibitor/antagonist mouse model neoplastic cell neutralizing antibody novel patient subsets pharmacodynamic biomarker predictive marker prevent receptor research study response small hairpin RNA sphingosine 1-phosphate sphingosine kinase targeted agent therapy resistant tumor tumor growth tumor xenograft

项目摘要

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.