Seminar given by Kumar Palle, Ph.D.
Mitchell Cancer Institute
University of South Alabama
Abstract: Ovarian cancer (OC) is the deadliest among all the gynecological malignancies, and represents fifth leading cause of cancer deaths worldwide. In USA alone over 15,000 women die each year. Indeed, most of the OC patients respond initially to cyrtoreductive surgery and platinum-based chemotherapy, but more than 70% of these patients present with recurrent disease, which is typically multidrug resistant and incurable. It is believed that recurrent tumors are largely due to a small population of cancer cells that dedifferentiated as cancer stem-like cells (CSC) or tumor-initiating cells. CSCs display quiescence, enhanced DNA damage tolerance and anti-apoptotic signaling to evade treatment, and capable of proliferating, differentiating back into tumor cells and reestablishing tumors once treatment is concluded. In order to identify the signaling mechanisms that promote acquired chemoresistance and CSC phenotype in OC, we conducted a pilot clinical study using matched pre- and post-chemotherapy ovarian tumors specimens and OC cell lines. Our combined analysis led to discover RAD6, a DNA repair protein that constitutes an E2 ubiquitin conjugating enzyme is significantly overexpressed in ovarian tumors and its expression increases in response to carboplatin chemotherapy. RAD6 expression correlated strongly with acquired chemoresistance and malignant behavior of OC cells, expression of stem cell genes and poor prognosis of OC patients. These results and the putative mechanisms combining RAD6 mediated DNA damage responses and signaling events leading to acquired chemoresistance and disease recurrence and its evaluation as a therapeutic target to prevent disease recurrence in OC and enhance the efficacy of standard chemotherapy will be discussed.
Room B36 COP/ Room E226 Rockford PHARM College of Pharmacy
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