Anti-angiogenic therapy with bevacizumab (BEV) is the most effective form of biologic therapy developed thus far for epithelial ovarian cancer (EOC). However, response is variable, BEV is expensive, and significant toxicity may occur. Given the projected increase in the global burden of cancer and limited health care resources it is imperative that research be conducted to define patients that will truly benefit from expensive therapies. The development of an angiogenic biomarker to direct the use of BEV could maximize benefit, as well as minimize toxicity and cost. My collaborator, Dr. Andrew Nixon, and his team at Duke have developed a plasma angiome that consists of 40 potential angiogenic biomarkers. We propose to evaluate the most promising (angiopoitin (Ang)-2, stromal cell-cell derived factor (SDF)-1, vascular endothelial growth factor (VEGF)-D, osteopontin (OPN), and interleukin (IL-6)) in women enrolled on the Gynecologic Oncology Group (GOG) 218 trial to determine if there is an association between angiogenic factors, survival, and BEV- resistance. The pivotal phase III GOG218 3-arm, placebo-controlled trial of front-line paclitaxel/carboplatin vs. BEV/paclitaxel/ carboplatin with and without maintenance BEV is the ideal platform to assess these biomarkers.
Our specific aims are to determine if Ang2, SDF-1, VEGF-D, OPN, and IL-6 are (1) predictive of progression-free and overall survival, and (2) will identify BEV-resistant disease in women with advanced EOC. We hypothesize that the focused angiome analysis will identify novel markers that predict for benefit from BEV, predict clinical outcome independent of treatment, and are associated with resistance. Baseline samples from GOG218 will be analyzed in Dr. Nixon's laboratory using the Searchlight system (Aushon Biosystems, Billerica, MA). Statistical analysis will be performed to identify and validate biomarkers of interest. Kaplan- Meier plots and log-rank tests will compare treatment groups. Subjects will be stratified based on BEV-resistant status to determine if there is an association between angiogenic factors and BEV-resistance. Our ultimate aim is to improve outcome for women with EOC by rationally directing BEV therapy;minimizing toxicity and cost;and identifying novel targets to develop future anti-angiogenic therapies.
This proposal seeks to identify biomarkers, using a novel plasma angiome that can be used to rationally direct BEV therapy in women with ovarian cancer. The successful completion of this project could alter the paradigm for the use of BEV as well as other anti-angiogenic agents in ovarian cancer;allow for rational and potentially cost-effective delivery of therapy;identify those destined to develop BEV-resistant disease;and identify novel targets that can be exploited to develop future anti-angiogenic therapies.