Overcoming Resistance to Anti-VEGF Treatment of Colorectal Cancers

抗血管生成治疗贝伐单抗与标准化疗联合治疗转移性结直肠癌（CRC）有效。然而，总体生存获益不大。在两项III期试验中，辅助贝伐单抗未能预防转移，这表明了CRC中抗血管生成治疗的进一步局限性。改善结直肠癌的预后需要克服阻碍抗VEGF治疗的耐药机制。临床研究一致认为，抗VEGF 治疗增加循环细胞因子水平。然而，这些分子的来源及其在CRC逃逸中的相关性仍然未知。我们发现抗VEGF治疗增加了CRC临床前模型中的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CXCR 4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著相关。基于 根据这些初步数据，我们假设VEGF阻断上调炎症途径如SDFI α和IL-6，其在VEGF阻断的情况下促进CRC生长并促进转移。我们假设阻断这些炎症通路将改善抗VEGF治疗的结果。我们将分析CRC间质中抗VEGF治疗诱导的细胞变化，并建立潜在的分子机制（目的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（目的2）。最后，我们将确定这些细胞因子在CRC中的作用 抗VEGF治疗后转移至肝和肺（目的3）。使用独特的实验技术，我们计划使用免疫活性同基因（移植）和自发（GEM）CRC模型来剖析CRC对抗VEGF治疗耐药的分子，细胞和生理机制-所有这些都密切概括了人类疾病表型。

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.