Endometriosis-associated ovarian clear-cell and endometrioid carcinomas are among the epithelial tumor subtypes with the lowest survival rates. Many of these tumors harbor mutations in factors that regulate molecular pathways associated with cell signaling and epigenetics. These pathways are predicted to provide epithelial cells with the ability to perceive, respond and adapt to environmental perturbations, such as tissue damage and inflammation. Moreover, these same perturbations or changes in cellular homeostasis are often introduced naturally during the ovarian and menstrual cycles and are beneficial in maintaining normal female reproductive health when regulated properly. We hypothesize that mutations in intracellular cell signaling and epigenetic factors cause the normal response to tissue damage and inflammation to go unchecked and promote some of the most deadly forms of ovarian cancer through increased chemotherapeutic drug resistance and prolonged tumor cell survival. These same inflammatory processes might be important for the transition from endometriosis to ovarian cancer, given the presence tumor-associated genetic lesions and inflammatory signatures in benign forms of the disease. In the proposal, we aim utilize genetically engineered mouse models of specific ovarian cancer subtypes if efforts to identify the mechanism by which cell signaling and epigenetic changes lead to the most severe forms of ovarian cancer and to provide the framework for the implementation of improved cancer prevention strategies and therapies targeting these homeostatic mechanisms. These studies will be invaluable at judging the benefit of combination therapies and identifying the potential biomarkers associated with early detection and drug efficacy.
Dr. Chandler received his Ph.D. in Molecular Physiology and Biophysics from Vanderbilt University. He was awarded a postdoctoral fellowship from the American Cancer Society to pursue postdoctoral research in the Laboratory of Dr. Terry Magnuson and Department of Genetics at the University of North Carolina at Chapel Hill. He is also previous recipient of an Ann and Sol Schreiber Mentored Investigator Award from the Ovarian Cancer Research Fund. Dr. Chandler is currently an Assistant Professor in Department of Obstetrics, Gynecology and Reproductive Biology at Michigan State University. His research interests include SWI/SNF chromatin remodeling-PI3-Kinase pathway crosstalk mechanisms and the role of epigenetics in ovarian cancer.