? ? 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 preclinical 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 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. 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112252-02
Application #
7222003
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Sorbara, Lynn R
Project Start
2006-04-14
Project End
2011-02-28
Budget Start
2007-04-17
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$376,466
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Jia, Jingquan; Dellinger, Andrew E; Weiss, Eric S et al. (2015) Direct Evidence of Target Inhibition with Anti-VEGF, EGFR, and mTOR Therapies in a Clinical Model of Wound Healing. Clin Cancer Res 21:3442-52