Role of Macrophages in Resistance to Anti-VEGF Drugs in Ovarian Cancer

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PROJECT SUMMARY (See instructions): The goal of SPORE Project 1 is to develop effective strategies for earty detection of ovanan cancer in women at average risk for the disease. Given the prevalence of ovanan cancer among postmenopausal women, a diagnostic strategy must be moderately sensitive (>75%), but highly specific (>99.6%) to achieve a positive predictive value of 10%, i.e., 10 laparotomies for each case of ovarian cancer detected. One of the most promising approaches to early detection of this neoplasm is to use rising values of a serum marker such as CA 125 to prompt the performance of transvaginal sonography (TVS). Patients with abnormal TVS or a sufficiently rapid rise in CA 125 undergo exploratory surgery. During the last grant period, we have evaluated this strategy and found a positive predictive value of 30%. If one is to pursue a two-stage strategy for earty detection, the initial stage must be optimally sensitive. No single marker is likely to be adequately sensitive and multiple markers may be required to detect the full spectrum of ovarian cancers. Simple addition of multiple markers may increase sensitivity, but generally decreases specificity, posing a particular problem in a disease with the prevalence of ovarian cancer. We have identified a panel of four biomarkers (CA125, HE4, CEA and sVCAM-1) that detect 87% of early stage disease at 98% specificity. In this project, our aims are Aim 1: To evaluate the specificity and positive predictive value of an algorithm for early detection of ovarian cancer based on a panel of serum biomarkers measured annually. Multiple biomarkers promise to increase sensitivity for earty stage and preclinical disease, provided that specificity is maintained, permitting performance of TVS in a small fraction of participants. We will test the hypothesis that rising values of multiple biomarkers will prompt the referral of no more than 2% of women for TVS and achieve a positive predictive value >10%. Aim 2: To develop a "point of service" test for multiple serum biomarkers using a lab-on-a-chip sensor system that is performed on blood from a finger-stick. Screening could be simplified if results were immediately available and venipuncture was not required. We will test the hypothesis that measurement of the levels of the four biomarkers with a lab-on-a-chip.nanosystem will correlate with standard laboratory assays. Aim 3: To identify a panel of serum autoantibodies for eariy detection of ovarian cancer. Small volumes of ovanan cancer may not release sufficient antigen to be detected, but could evoke an antibody response. We will test the hypothesis that detection of autoantibodies to mutant and wild-type proteins will improve detection of ovarian cancers that do not elevate antigen levels.