Anti-VEGF in Tumors & Wounds: Efficacy vs Toxicity

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Abstract The clinical importance of anti-VEGF therapy has recently been validated with the positive phase III results of bevacizumab in metastatic colorectal cancer. However, bevacizumab may have side effects such as increased risks of GI perforation, peri-operative wound healing complications, and arterial vascular events. All of these toxicities may be related to the role of VEGF in wound healing biology. Angiogenic responses in tumors and wounds utilize very similar cellular, matrix, and growth factor components and wound healing gene expression profiles are conserved between granulation tissue and multiple tumor types. To exploit these similarities and to understand the effects of angiogenesis inhibitors on wound healing, we have developed a safe and convenient clinical dermal wound angiogenesis assay. Based upon preclincial resistance mechanisms, the efficacy and toxicity profile of bevacizumab in the clinic, and our preliminary preclinical and clinical data, and using paired pre and on treatment tumor and wound biopsies, we will test the hypothesis that bevacizumab treatment will have the following molecular andphysiological consequences in both tumors and wounds in patients. Anti-VEGF therapy will (1) inhibit VEGFR2 phosphorylation, (2) inhibit neovascularization; 3) upregulate compensatory VEGF ligands and receptors; (4) uregulate compensatory non-VEGF angiogenic factors; and (5) upregulate specific angiogenic gene expression profiles. Lastly, we hypothesize that these effects will be highly correlated in both tumors and wounds. Taken together, this work will establish whether wound angiogenesis can serve as a clinical mechanism-based biomarker for anti-VEGF therapies. These studies will determine which effects of anti-VEGF therapy in tumors and wounds are similar and distinct, with a focus on mechanisms of sensitivity, toxicity, and resistance that are targetable. This work has the potential to improve both the safety and efficacy of this novel class of drugs. I; '