In North America, one in seven men will be diagnosed with prostate cancer. Although effective surgical and radiation treatment exists for clinically localized prostate cancer, in about 25% of patients the tumors continue to grow and spread throughout the body. These cancers remain essentially incurable and are the focus for this proposed research project. While new drugs, the most notable being one called enzalutamide, have been developed to treat these patients their effect is short-lived; tumors can develop resistance to these drugs and grow back, sometimes stronger than before, making this a major medical problem. Our laboratory has recently identified an ominous and possibly widespread way for prostate cancer to progress after treatment with enzalutamide. It turns out that cancer cells can be re-educated and emerge as 'cancer stem cells' that can survive and proliferate in the presence of enzalutamide. We identified a protein called EZH2 that we believe controls this process. To investigate its importance we will isolate tumor DNA from the blood of patients progressing on anti-androgen therapy to analyze changes in the EZH2 protein. Moreover, we will manipulate its expression and study the effect on the cancer stem cells as well as tumor growth. This knowledge will guide the design of pre-clinical studies to test drugs that could turn off EZH2 to cure, or at least slow the progression of prostate cancer. Our studies are focused on investigating a number of drugs that are already in clinical trials and, as such, could be "re-purposed" for use in prostate cancer patients, thereby decreasing the time to achieve a patient-related outcome from decades to years. It is our hope that this research will open up the possibility that combining enzalutamide with a drug that inhibits EZH2 (or another drug that targets cancer stem cells) could be a promising treatment approach that will improve survival and quality of life for patients with aggressive prostate cancer.