Grant: Operating Grant

Despite recent advances in cancer research, ovarian cancer remains one of the most lethal forms of cancer, due primarily to late diagnosis and to loss in responsiveness to chemotherapy (chemoresistance). Ovarian cancer is commonly treated with the drug cisplatin, and while many patients initially respond, chemoresistant tumours frequently recur. However, the precise mechanisms by which chemoresistance develops are not well understood. Most chemotherapeutic drugs function by inducing programmed cell death (apoptosis) of the cancer cells, thereby eradicating the tumour, and recent evidence suggests that dysregulation of apoptosis may be an important factor for chemoresistance. The overall objective of the proposed research program is to improve our understanding of the underlying mechanisms of chemoresistance. We hypothesize that chemosensitivity of ovarian cancer cells is determined by the ability of the tumor suppressor p53 to be activated and to target the cellular organelles and induce apoptosis. Gelsolin, a intracellular protein associated with the cellular structural network (cytoskeleton) is believed to be important in the regulation of apoptosis, if and how it play an important role in the control of chemosensitivity in ovarian cancer is not well understood. These processes are modulated by the enzyme Akt in chemoresistant ovarian cancer cells. The proposed program will provide new insight into how chemoresistance occurs, and valuable information for the development of new chemotherapeutic agents and gene targeting strategies to combat this deadly disease.