Overcoming Resistance to Anti-VEGF Treatment of Colorectal Cancers

克服结直肠癌抗 VEGF 治疗的耐药性

• 批准号: 8463132
• 负责人: Dai Fukumura
• 金额: $ 24.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463132
• 关键词: Adjuvant; Blood; Blood Vessels; Bone Marrow; CXCR4 Receptors; Cancer Model; Cancer Patient; Cells; Clinical; Clinical Research; Colorectal Cancer; Data; Distant; Distant Metastasis; FDA approved; Failure; Functional disorder; Genetically Engineered Mouse; Growth; Hypoxia; Immunocompetent; Inflammatory; Instruction; Interleukin-6; Life; Liver; Localized Disease; Luciferases; Lung; Measures; Molecular; Monitor; Myelogenous; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phase III Clinical Trials; Physiological; Plasma; Pre-Clinical Model; Rectal Cancer; Recurrence; Resistance; Role; Solid Neoplasm; Source; Stromal Cells; Techniques; Technology; Tissues; Transplantation; Tumor Tissue; Up-Regulation; Vascular Endothelial Growth Factors; angiogenesis; base; bevacizumab; cancer therapy; chemotherapy; cytokine; disease phenotype; human disease; improved; metastatic colorectal; novel; pre-clinical; prevent; resistance mechanism; tumor; tumor growth

The anti-angiogenic therapy bevacizumab is efficacious in metastatic colorectal cancers (CRCs) when combined with standard chemotherapy. However, overall survival benefit is modest. A further limitation of anti-angiogenic treatment in CRCs was represented by the failure of adjuvant bevacizumab to prevent metastasis in two phase III trials. Improving the outcome in CRC will require overcoming the resistance mechanisms that thwart the anti-VEGF therapy. Clinical studies converged to the observation that anti-VEGF therapy increases circulating cytokine levels. However, the source of these molecules and their relevance in CRC escape remains unknown. We found that anti-VEGF therapy increases SDFIa and IL-6 in preclinical models of CRC. These data are consistent with the upregulation of SDFIa and its receptor CXCR4 in rectal carcinoma patients treated with bevacizumab. In these patients, higher SDFIa and IL-6 plasma levels during bevacizumab treatment were significantly associated with local recurrence and distant metastases. Based on these preliminary data, we hypothesize that VEGF blockade upregulates inflammatory pathways such as SDFIa and IL-6 which fuel CRC growth and promote metastasis in the face of VEGF blockade. We hypothesize that blocking these inflammatory pathways will improve outcomes of anti-VEGF therapy. We will analyze the cellular changes induced by anti-VEGF therapy in CRC stroma and establish the underlying molecular mechanisms (Aim 1). We will then determine the causal role of SDFIa and IL-6 pathways in CRC growth after anti-VEGF treatment (Aim 2). Finally, we will establish the role of these cytokines in CRC metastasis to the liver and lung after anti-VEGF treatment (Aim 3). Using unique experimental technologies, we plan to dissect these molecular, cellular and physiological mechanisms underlying resistance to anti-VEGF therapy in CRC using immunocompetent syngeneic (transplanted) and spontaneous (GEM) CRC models - all of which closely recapitulate the human disease phenotype.

抗血管生成疗法贝伐珠单抗与标准化疗联合使用对转移性结直肠癌 (CRC) 有效。然而，总体生存获益不大。结直肠癌抗血管生成治疗的另一个局限性是贝伐珠单抗辅助治疗在两项 III 期试验中未能预防转移。改善结直肠癌的治疗效果需要克服阻碍抗 VEGF 治疗的耐药机制。临床研究集中观察抗 VEGF 治疗会增加循环细胞因子水平。然而，这些分子的来源及其与 CRC 逃逸的相关性仍然未知。我们发现抗 VEGF 治疗可增加 CRC 临床前模型中的 SDFIa 和 IL-6。这些数据与接受贝伐单抗治疗的直肠癌患者中 SDFIa 及其受体 CXCR4 的上调一致。在这些患者中，贝伐单抗治疗期间较高的 SDFIa 和 IL-6 血浆水平与局部复发和远处转移显着相关。基于 根据这些初步数据，我们假设 VEGF 阻断会上调炎症通路，例如 SDFIa 和 IL-6，这些通路在 VEGF 阻断的情况下会促进 CRC 生长并促进转移。我们假设阻断这些炎症途径将改善抗 VEGF 治疗的结果。我们将分析抗 VEGF 治疗在 CRC 基质中诱导的细胞变化，并建立潜在的分子机制（目标 1）。然后，我们将确定抗 VEGF 治疗后 SDFIa 和 IL-6 通路在 CRC 生长中的因果作用（目标 2）。最后，我们将确定这些细胞因子在 CRC 中的作用 抗 VEGF 治疗后转移至肝脏和肺部（目标 3）。利用独特的实验技术，我们计划使用具有免疫活性的同基因（移植）和自发（GEM）CRC 模型来剖析这些 CRC 抗 VEGF 治疗耐药的分子、细胞和生理机制，所有这些模型都密切再现了人类疾病表型。