The anti-angiogenic therapy bevacizumab is efficacious in metastatic colorectal cancers (CRCs) whenb 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.
Anti-angiogenic therapy was first approved by the FDA for metastatic colorectal cancer treatment. However, its benefit appears to be modest and short-lived in cancer patients with localized disease. Here we propose to establish strategies to overcome colorectal cancer resistance to anti-angiogenic therapy that leads to local and distant progression.
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