The major reported cause of ovarian cancer mortality is resistance to conventional chemotherapies which in turn promotes cancer metastasis. Most ovarian cancer patients who were initially responsive to standard chemotherapeutic regimens will inevitably relapse with metastasis, recurrence, and drug resistance. Although women diagnosed with the localized disease have a 90% likelihood of 5-year survival, most patients diagnosed with advanced stage disease develop recurrent disease after initial therapy and succumb to the progressive disease. While treatment with cytoreductive surgery and chemotherapy have proven effective, most women eventually suffer disease recurrence and eventual death. The progressive growth of primary tumor and metastasis is highly dependent on angiogenesis. Therefore, new therapeutic strategies are needed to improve patient outcomes. New anti-cancer therapies have targeted neovascularization because of the increasingly recognized role of angiogenesis in tumor progression. Anti-vascular endothelial growth factor (anti-VEGF) therapies were reported to show great benefits in preclinical and clinical trials and are approved drugs along with conventional chemotherapeutics. Even though they are a great promise, their efficacy has been modest due to the emergence of drug resistance. Bevacizumab (monoclonal antibody against VEGF-A) was among the first anti-angiogenic agents developed and has provided clinical benefit in several solid tumor types. Anti-angiogenic therapy with bevacizumab along with chemotherapy is an approved regimen in the U.S.; however, most tumors rapidly adapt and develop resistance to such drugs. Drug resistance is multi-factorial process that can arise, in part, due to alterations in pharmacokinetics, cell-specific abnormalities, methylation and changes in the tumor microenvironment. It has been now established that aberrant DNA methylation plays a crucial role, together with genetic alterations, in tumorigenesis and tumor maintenance. There are also various reported studies shows the beneficial effects of hypomethylating agents in the treatment of cancers. DNA methylation inhibitors 5-Azacytidine and 5-Aza-2’-deoxycytidine have been increasingly used in the clinic to treat myeloid disorders and cancer since their FDA approval over a decade ago.
In the present study, we focused on the additive effect of an anti-VEGF antibody, B20, and a DNA methylation inhibitor, 5-Azacytidine to overcome the tumor resistance to anti-VEGF therapy. Our preliminary data suggest that epigenetic therapy in the tumor microenvironment play a significant role in reversing such resistance. Importantly, our data suggest that resistance to anti-VEGF therapy can be reversed by azacitidine. These findings prompted us to hypothesize that addition of a hypomethylating agent can reverse resistance to anti-VEGF therapy in ovarian cancer. This work has substantial clinical implications including identification of predictive markers for response to anti-VEGF therapies and potential use of demethylating drugs for reversing resistance to anti-angiogenesis