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: 8517017
• 负责人: CHRISTOPHER G. WOOD
• 金额: $ 24.45万
• 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 2015-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517017
• 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为抑制VEGF的抗肿瘤药物， 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）已经产生了深刻的影响。 对转移性肾细胞癌（RCC）患者管理的影响。但尽管 这些药物延长PFS的能力，在某些情况下，诱导部分肿瘤消退，大多数情况下， 的RCC患者在6-12个月内对这些药物产生耐药性。在先前的小鼠异种移植研究中 使用786-0和A498细胞系，我们已经确定抗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RCC中鉴定出几种基因和蛋白质，其表达随着 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几个 候选蛋白/途径，基于它们在肿瘤进展和/或血管生成中的已知作用， 可能有助于耐药性的发展。我们现建议将这些研究扩展至： 在接受舒尼替尼治疗的RCC患者中验证我们的小鼠组织、血液和成像结果 治疗; 2）评估这些蛋白质/途径的药理学抑制剂延迟或 在涉及786.0和A498的皮下植入异种移植物中防止对舒尼替尼的耐药性; 3） 使用STC和灌注评估皮下和原位异种移植物中有希望的组合 显像这些研究将为舒尼替尼联合 基于其阻断一种或多种关键信号传导途径的能力而选择的其它药剂 导致舒尼替尼耐药。终点将包括通过MRI和连续成像测量的肿瘤灌注变化。 细胞因子水平和延缓疾病进展。总的来说，这些研究将阐明机制 RCC对VEGFR阻断产生耐药性，并确定可能 规避这个问题。