Evaluation of antiangiogenic and antimetabolic drugs as a combination therapy in patient derived xenografts of ovarian cancer

Ovarian cancer is the seventh most diagnosed cancer among women, and it is considered the most lethal gynaecologic malignancy. Standard treatment strategies are primary cytoreductive surgery and chemotherapy, but 70% of patients with advanced stage disease shows recurrence and develops drug resistance. Angiogenesis inhibitors that target vascular endothelial growth factor A (VEGF-A), such as bevacizumab, are used to block tumor growth, but eventually resistance occurs. Antiangiogenic agents alter nutrients availability and cause energy imbalance, affecting metabolic features of tumor cells. Targeting metabolic dependencies could overcome resistance to antiangiogenic therapy. In this thesis, we show that bevacizumab alters ascites’ glucose concentration in patient-derived xenografts of ovarian cancer. We found that sensitivity or resistance to glucose-deprivation in our models associated with different responses to treatment with antiangiogenic and antimetabolic drugs. Finally, we demonstrated that metformin treatment could be used as a synthetic lethal approach in combination with bevacizumab in our models in vivo. Taken together, our findings suggest that combining bevacizumab and metformin could be a potential treatment strategy in ovarian cancer patients.