The goal of this proposal is to support innovative patient oriented translational research through 1) developing tissue based biomarkers to guide the development of anti-angiogenesis drugs, and 2) development and mentoring of junior clinical researchers. The importance of anti-VEGF therapy has been validated in a phase III clinical trial of bevacizumab in patients with 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. These toxicities may be related to the role of VEGF in wound healing. Angiogenic responses in tumors and wounds utilize similar cellular, matrix, and growth factor components. Also, wound healing gene expression profiles are conserved between granulation tissue and multiple tumor types. To exploit these similarities and understand the effects of angiogenesis inhibitors on wound healing, we have developed a safe and convenient dermal wound angiogenesis assay. Based upon preclinical resistance mechanisms, the efficacy and toxicity profile of bevacizumab in the clinic, and our preliminary preclinical and clinical data, we will use paired pre- and on- treatment tumor and wound biopsies to test the hypothesis that bevacizumab treatment will have the following molecular and physiological 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) upregulate compensatory non-VEGF angiogenic factors; and 5) upregulate specific angiogenic gene expression profiles. We hypothesize that these effects will be highly correlated in both tumors and wounds. This project 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. ? ? In the context of this work, junior investigators will be trained in clinical research related to anti-angiogenesis agents. Trainees will have specific educational and research experiences, including the development and oversight of several biomarker studies. ? ? ?
Showing the most recent 10 out of 20 publications
