Ovarian cancer is the fifth leading cause of deaths in women with all cancer and the most lethal gynecologic malignancy, with more women dying from this disease than all other gynecologic cancer combined. In 2010, approximately 22,000 women will be newly diagnosed with ovarian cancer and ~15,000 will die from this disease in the United States alone. Lack of effective early detection methods and the development of resistance to first-line chemotherapeutics leave few options for the clinical management of ovarian cancer, particularly advanced ovarian cancer. Although 80% of women initially respond to the combination of platinum and taxane-based treatment, the majority of them relapse due to the development of drug resistance. Therefore, circumventing tumor resistance to commonly used first-line agents represents a very important aspect of multiple initiatives to eliminate ovarian cancer, which could result in improved survival and ultimately enhance the quality of life in women with advanced ovarian cancer. Through the collaborative efforts of gynecologic oncologist, cancer biology scientist, and geneticist using state-of-art technologies, the objectives of our proposed work is to develop a novel strategy to predict patient's response to chemotherapy based on the expression profile of a new class of molecules called microRNA (miRNA) and identify potential miRNA targets in order to overcome chemoresistance. Over the last decade, accumulating evidence shows that miRNAs play a critical role in the regulation of gene and protein expression in human disease, with several hundreds of known miRNAs capable of simultaneously modulating the expression of approximately one-third of the genome. Given their prevalence and complex nature, miRNAs represent an attractive candidate to target and thereby prevent the many processes that may lead to ovarian cancer chemoresistance.

Our proposed research, if successful, will help women who are newly diagnosed with late-stage ovarian cancer in two major ways: (1) genetic profiling of key miRNAs associated with chemoresistance validated in our research will help predict patients' responses to clinically available first-line agents and thus provide guidance for the selection of tailored chemotherapeutic regimens in order to decrease the incidence of recurrence; (2) adjuvant therapy using drugs targeting resistance-associated miRNA will enhance the sensitivity of tumor response to first-line agents and ultimately improve survival. As mounting evidence suggests the potential roles of miRNA in the regulation of cancer-related gene networks and the involvement in cancer initiation and progression, we expect our research will identify predictive markers for chemoresponse and identify novel targets for developing miRNA-targeted therapeutics. With the projected benefits of improving ovarian cancer response to chemotherapy and reducing the burden of ovarian cancer, our study is not without risks. Since the identification of first miRNA in 1993, miRNA remains a relatively new class of molecules with a lot of their biological roles not fully understood. Because each miRNA regulates the expression of hundreds of target genes involved in human physiology and pathology, some off-target inhibition not specific to the chemoresistance-related genes may lead to side effects when used as therapeutic target. However, as we build our understanding of the biological and functional roles of each chemoresistance-associated miRNA, we are confident that a new drug targeting miRNA to enhance chemosensitivity will be validated within the next 5 to 10 years and unique drug-specific resistance-associated miRNA signatures will be used as predictive markers to direct the selection of first-line agents and monitor disease progression in the next 2 to 5 years. The power of our approach to identify miRNAs associated with chemoresistance resides in our team's ability to perform comprehensive characterization of miRNA signatures in ovarian cancer followed by the functional consequences in vivo using a state-of-the-art mouse model of ovarian cancer. This combination of functional and molecular characterization of relevant miRNAs will allow for the rapid discovery and validation of novel signaling pathways driving ovarian cancer chemoresistance and the development of new treatments for this deadly disease.