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.
Xin Huang, Ph.D. is an Assistant Professor at Magee-Womens Research Institute of The University of Pittsburgh School of Medicine Department of Obstetrics, Gynecology, and Reproductive Sciences. He received his undergraduate degree in Microbiology from Sichuan University, and Master degree in Genetics from Fudan University, both in China. He then went on to receive his Ph.D. in Human Genetics from the University of Pittsburgh Graduate School of Public Health. After a short Postdoc at the University of Pittsburgh Cancer Institute, he subsequently came to Stanford University for Postdoctoral training in the Department of Radiation Oncology where he studied the mechanism of microRNA expression regulated by tumor hypoxia. He has received the American Cancer Society Research Scholar Award for his research. Currently, the research in his laboratory is focused on identifying biomarkers for ovarian cancer early detection and understanding the function of a hypoxia-regulated microRNA, miR-210, in ovarian cancer tumorigenesis. The long-term goal of his laboratory is to improve the overall survival of ovarian cancer patients through early detection and developing novel therapeutic targets.