Overcoming Resistance to Anti-VEGF Treatment of Colorectal Cancers

贝伐单抗联合标准化疗对转移性结直肠癌有效。然而，总体生存收益并不大。在两个III期试验中，佐剂贝伐单抗未能预防肿瘤转移，这是抗血管生成治疗的进一步限制。改善结直肠癌的治疗结果需要克服阻碍抗血管内皮生长因子治疗的耐药机制。临床研究集中在观察到抗血管内皮生长因子 治疗可提高循环细胞因子水平。然而，这些分子的来源及其与结直肠癌逃逸的相关性仍不清楚。我们发现，在临床前结直肠癌模型中，抗血管内皮生长因子治疗增加了SDFIa和IL-6。这些数据与贝伐单抗治疗直肠癌患者SDFIa及其受体CXCR4的上调是一致的。在这些患者中，贝伐单抗治疗期间较高的SDFIa和IL-6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，我们假设在阻断血管内皮生长因子的情况下，阻断血管内皮生长因子上调了炎症通路，如SDFIa和IL-6，从而促进了结直肠癌的生长和转移。我们假设阻断这些炎症通路将改善抗血管内皮生长因子治疗的结果。我们将分析抗血管内皮生长因子治疗对结直肠癌间质细胞的影响，并建立其潜在的分子机制(目标1)。然后，我们将确定SDFIa和IL-6通路在抗血管内皮生长因子治疗后结直肠癌生长中的因果作用(目标2)。最后，我们将确定这些细胞因子在结直肠癌中的作用。 抗血管内皮生长因子治疗后的肝和肺转移(目标3)。利用独特的实验技术，我们计划使用免疫活性的同基因(移植)和自发性(GEM)结直肠癌模型来剖析结直肠癌抵抗抗血管内皮生长因子治疗的分子、细胞和生理机制--所有这些模型都紧密地概括了人类疾病的表型。

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.