Overcoming Resistance to Anti-VEGF Treatment of Colorectal Cancers

克服结直肠癌抗 VEGF 治疗的耐药性

基本信息

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
项目类别：
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

项目摘要

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单抗与标准化学疗法结合使用时在转移性结直肠癌（CRC）中有效。但是，总体生存益处是适中的。在CRC中，抗血管生成治疗的进一步局限是通过辅助贝伐单抗在两阶段III试验中预防转移的失败来表示。改善CRC的结果将需要克服阻碍抗VEGF治疗的抗药性机制。临床研究融合了抗VEGF的观察治疗增加了循环的细胞因子水平。但是，这些分子的来源及其在CRC逃生中的相关性仍然未知。我们发现，在CRC的临床前模型中，抗VEGF疗法会增加SDFIA和IL-6。这些数据与用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。基于这些初步数据，我们假设VEGF阻塞上调了诸如SDFIA和IL-6之类的炎症途径，这些途径在VEGF阻断面前为CRC增长并促进转移。我们假设阻止这些炎症途径将改善抗VEGF治疗的预后。我们将分析CRC基质中抗VEGF治疗引起的细胞变化，并建立潜在的分子机制（AIM 1）。然后，我们将确定抗VEGF处理后SDFIA和IL-6途径在CRC生长中的因果作用（AIM 2）。最后，我们将确定这些细胞因子在CRC中的作用抗VEGF治疗后向肝脏和肺转移（AIM 3）。使用独特的实验技术，我们计划使用免疫能力的合子（移植）和自发性（GEM）CRC模型来剖析CRC中对抗VEGF治疗的抗药性的这些分子，细胞和生理机制 - 所有这些模型都严密地概括了人类疾病现象。