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: 8322742
• 负责人: CHRISTOPHER G. WOOD
• 金额: $ 24.9万
• 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/8322742
• 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 批准了几种抗肿瘤药物，其主要作用方式是抑制 VEGF 受体 2 信号传导和肿瘤血管生成的破坏（例如舒尼替尼、索拉非尼）具有深远的影响 对转移性肾细胞癌（RCC）患者治疗的影响。然而，尽管 这些药物能够延长 PFS，并且在某些情况下诱导部分肿瘤消退，大多数 的 RCC 患者在 6-12 个月内对这些药物产生耐药性。在之前的小鼠异种移植研究中 使用 786-0 和 A498 细胞系，我们已经确定耐药性可能与血管生成逃逸有关。 来自这些 RCC 细胞系和短期培养物 (STC) 异种移植物的 cDNA 微阵列和蛋白质印迹 从新鲜收获的人类 RCC 中鉴定出一些基因和蛋白质，其表达被改变 对舒尼替尼/索拉非尼产生耐药性。这些基因表达研究提供了一些 候选蛋白质/途径，基于其在肿瘤进展和/或血管生成中的已知作用， 可能有助于耐药性的发展。我们现在建议扩大这些研究范围，包括：1) 在接受舒尼替尼治疗的肾细胞癌患者中验证我们的小鼠组织、血液和影像学结果 治疗; 2) 评估这些蛋白质/途径的药理学抑制剂延迟或延迟的能力 防止皮下植入的异种移植物对舒尼替尼产生耐药性，涉及 786.0 和 A498； 3） 使用 STC 和灌注评估皮下和原位异种移植中有希望的组合 成像。这些研究将为舒尼替尼联合用药的多项临床试验奠定基础 根据其阻断一个或多个关键信号通路的能力而选择的其他药物 导致舒尼替尼耐药。终点将包括通过 MRI 和序列检查发现的肿瘤灌注变化 细胞因子水平，并延缓疾病进展。总的来说，这些研究将阐明其机制 RCC 对 VEGFR 阻断产生耐药性并确定可能的治疗策略 规避这个问题。