Mechanism of evasion by ovarian cancers from anti-VEGF therapy

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PROJECT SUMMARY The majority of women who are diagnosed with ovarian cancer present with ascites and disseminated disease and relapse within 18 months after conventional platinum-based chemotherapy. Bevacizumab is a humanized antibody that was approved in 2014 for treating platinum-resistant recurrent ovarian cancer and has also been found to increase progression-free survival when combined with conventional chemotherapy as front-line treatment. Bevacizumab neutralizes vascular endothelial growth factor-A (VEGF), a growth factor that has well- established roles in stimulating endothelial cell survival, migration and vessel formation and also causes ascites accumulation. However, not all patients respond to bevacizumab and there are no biomarkers that can reliably distinguish patients who are likely to benefit from this therapy from those who will not. We have extensively investigated the mechanisms that control ovarian tumor progression, in particular the interactions between ovarian cancer cells and constituents of the tumor stroma. Based on our preliminary studies, we hypothesize that resistance to bevacizumab might stem in part from the ability of ovarian cancer cells to produce small vesicles called exosomes that act as a `Trojan Horse' to deliver VEGF to endothelial cells without being neutralized by bevacizumab. In Aim 1 of this project, we will validate the presence of exosomal VEGF in ovarian cancer patients, determine the signaling mechanism of exosomal VEGF, and evaluate the ability of exosomal VEGF to stimulate ovarian tumor angiogenesis and ascites formation in xenograft models. In Aim 2, we will evaluate the ability of bevacizumab to block exosome-induced ovarian tumor angiogenesis and ascites formation, and evaluate the relationship between levels of exosomal VEGF and responses to bevacizumab in ovarian cancer xenograft models and ovarian cancer patients. Our study addresses the critical need for biomarkers that could guide the selection of ovarian cancer patients for whom bevacizumab treatment is most beneficial and will also provide new insights for designing more effective anti-angiogenic therapies.