Ovarian cancer is the leading cause of death among gynecologic cancers. Primary focus of our laboratory is to understand the biology of ovarian cancer and develop novel therapeutic strategies. Ovarian cancer growth is accompanied by the development of malignant ascites in the peritoneum. Ascites exposes the tumor cells to persistent hypoxia. Hypoxic microenvironment provides a sanctuary to tumor initiating cancer cells and induce resistance to chemotherapy. Hypoxia also initiates peritoneal seeding and metastasis of ovarian cancer cells. Therefore, understanding hypoxia-induced adaptive changes in cancer cells is important to develop effective cancer treatment. Our studies have shown a network of microRNAs regulating hypoxia induced factor-1(HIF-1alpha), a pivotal transcription factor driving the expression of proangiogenic growth factors, metabolic reprogramming and increased cell motility. We have genetically deleted hypoxia-induced microRNA (knockout) in mice and currently investigating the loss of function of microRNA on angiogenesis, tumor growth and metastasis.
Survival of cancer patients is inversely correlated with tumor hypoxia. Therefore, methods to intervene hypoxic adaptation of cancer cells will overcome therapeutic resistance, prevent metastasis and improve survival of cancer patients. Our studies have established a close relationship between oxygen and iron levels in cancer cells. Iron homeostasis is an attractive target for cancer therapy. Intracellular iron acts as a catalyst in the formation of hydroxyl and hydroperoxy radicals via the Fenton Reaction. These free radicals can induce lipid peroxidation and membrane damage in addition to inducing DNA damage. Our preliminary studies have shown that iron synergizes with platinum and other DNA-damaging drugs, such as Doxorubicin, cyclophosphamide, and etoposide. Furthermore, treatment of athymic mice with iron and platinum drug, synergistically inhibited tumor growth and increased survival. Based on these studies, we propose to investigate the use of a clinically approved, non-toxic formulation of iron and iron nanoparticles to improve therapeutic efficacy of cancer drugs in preclinical models of cancer.
Tumor hypoxia favors the establishment of an immunosuppressive microenvironme('co ld tumors'). and prevents immune surveillance against cancer cells. Our laboratory has developed a self-anchoring immunostimulatory molecule by genetically engineering T-cell receptor binding domain of a superantigen, TSST1. Superantigen-coated tumor cell vaccines convert 'cold tumors' to 'hot tumors' by attracting effector T-cells into the tumors. We are currently evaluating the therapeutic efficacy of superantigen coated cancer vaccines either alone or in combination with anti-angiogenic and chemotherapeutic drugs in preclinical models.