P3 - Acquired Resistance to VEGF Receptor Blockade: Underlying Mech & Therapeuti

P3 - 对 VEGF 受体阻断的获得性耐药：潜在机制

• 批准号: 8381283
• 负责人: CHRISTOPHER G. WOOD
• 金额: $ 26.24万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8381283
• 关键词: Acute; Animal Model; BAY 54-9085; Biopsy; Blood; CXCR4 gene; Cell Line; Clinical Trials; Dana-Farber Cancer Institute; Data; Disease; Disease Progression; Endothelium; Exhibits; Gene Expression; Gene Proteins; Harvest; Human; Hypoxia; Image; Implant; Link; Magnetic Resonance Imaging; Malignant Epithelial Cell; Measures; Mediator of activation protein; Metastatic Renal Cell Cancer; Modeling; Mus; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Phase; Physiological Adaptation; Pilot Projects; Plasma; Proteins; Receptor Signaling; Renal Cell Carcinoma; Renal carcinoma; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Stress; Testing; Time; Tissue Sample; Tissues; Tumor Angiogenesis; Validation; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Xenograft Model; Xenograft procedure; angiogenesis; antitumor agent; base; bevacizumab; cDNA Arrays; cytokine; design; inhibitor/antagonist; meetings; prevent; response; sphingosine kinase; subcutaneous; treatment strategy; tumor; tumor growth; tumor progression

The recent FDA approval of several antitumor agents whose primary mode of action is the inhibition of VEGF receptor-2 signaling and the disruption of tumor angiogenesis (e.g. sunitinib, sorafenib) has had a profound impact on the management of patients with metastatic renal cell carcinoma (RCC). However, despite the ability of these agents to prolong PFS and in some instances, to induce partial tumor regression, the majority of RCC patients develop resistance to these agents within 6-12 months. In previous murine xenograft studies using 786-0 and A498 cell lines we have established that resistance is likely related to angiogenic escape. cDNA microarray and westerns with from xenografts of these RCC cell lines and short-term cultures (STCs) from freshly harvested human RCC identified several genes and proteins whose expression is altered with the development of resistance to sunitinib/sorafenib. These gene expression studies provide several candidate proteins/pathways that, based on their known role in tumor progression and/or angiogenesis, are likely to contribute to the development of resistance. We now propose to extend these studies to include: 1) validation of our murine tissue, blood and imaging findings in patients with RCC undergoing sunitinib therapy; 2) assessment of the ability of pharmacologic inhibitors of these proteins/pathways to either delay or prevent resistance to sunitinib in subcutaneously implanted xenografts involving 786.0 and A498; 3) assessment of promising combinations in subcutaneous and orthotopic xenografts using STCs and perfusion imaging. These studies will lay the groundwork for several clinical trials with sunitinib in combination with other agents selected on the basis of their ability to block one or more critical signaling pathway that might contribute to sunitinib resistance. Endpoints will include changes in tumor perfusion by MRI and serial cytokine levels, and delay in disease progression. Collectively, these studies will elucidate the mechanism by which RCC develops resistance to VEGFR blockade and identify treatment strategies that might circumvent this problem.

最近FDA批准了几种主要作用方式是抑制VEGF的抗肿瘤药物