Epithelial ovarian cancer is the deadliest gynecological cancer in women and the fifth leading cause of cancer death in women in the United States. Currently, the combination of carboplatin and paclitaxel is the preferred standard chemotherapeutic drugs in treating ovarian cancer diagnosed at late stages. However, tumor recurrence and the emergence of drug-resistant disease are common in patients with advanced disease. Because of this, the five-year survival of late-stage EOC patients has remained at approximately 30% despite considerable effort in clinical and basic researches. At present, the successful treatment of EOC patients still remains a medical challenge. Therefore, identifying new therapeutic targets for more efficient EOC treatment is in great need.
Oxygen is essential for our survival and there is no exception for cells inside human body, including cancer cells. Because cancer cells grow uncontrollably, they can outgrow their blood supply, causing certain area lacking of oxygen, named hypoxia. Because hypoxic tumor cells are resistant to chemotherapy and radiation therapy, cancer patients with hypoxic tumors usually have worse survival and poor prognosis. Ovarian tumors also contain hypoxic regions, which directly contribute to the dismal survival of ovarian cancer patients. Energy supply is fundamental to cell growth and survival. Oxygen is required for efficient cellular energy generation. In cells, energy is mainly generated at a place called mitochondria, which are also called the “energy factories” of a cell. Therefore, hypoxic ovarian tumor cells have to rely on a less efficient pathway, termed glycolysis, for energy production. The reliance of hypoxic tumor cells on glycolysis creates an opportunity to targeting this pathway that can specifically kill these cells.
Our long term goal is to understand the molecules and mechanisms that control hypoxic tumor cell energy production and to exploit these mechanisms as the “weakest links” in ovarian tumor cells to eliminate them. Toward this aim, we have examined the function of a small RNA molecule, named miR-210, that is highly induced by hypoxia in ovarian tumor cells. We have found that miR-210 can regulate a critical component of the mitochondria energy production chain called NDUFA4 and therefore, influence ovarian cancer cell energy production. In this proposal, we will investigate the ways miR-210 in regulating mitochondrial metabolism, especially how miR-210 regulates glycolysis, and explore whether we can target miR-210 for ovarian cancer therapy in mice. Ultimately, we’d like to translate this knowledge into new ways of treating ovarian cancer patients. Because of the widespread phenomenon of tumor hypoxia, the discovery made in this proposed study can be potentially applied to targeting all solid tumors.