The Role of EZH2 in High-Risk Non-Muscle Invasive Bladder Cancer

Joshua Meeks is a urologic oncologist with the career training in the laboratory and clinical medicine to become a physician-scientist. His goal is to improve the survival and quality of care for patients with bladder cancer through translational work on genetic research. Physicians (and even less often surgeons) are rarely able to develop both a productive clinical practice and achieve significant academic gains- yet Dr. Meeks’ career is forged on the integration of these two areas. In order to protect his time from clinical demands, fund the research critical to his success and provide additional training in epigenetics and pathology of bladder cancer, Dr. Meeks must obtain funding in the form of a career-development award. The ultimate goal of this research is 1) to development novel diagnostic biomarkers for non-muscle invasive bladder cancer and 2) determine the role of EZH2 in bladder cancer for a therapeutic target. For patients with non-muscle invasive cancer, recurrence is far more common a problem than progression to invasion. Yet, some of these tumors will invade the bladder wall and early aggressive therapy will improve survival by decreasing the risk of progression to pelvic lymph nodes. We will evaluate the role of EZH2 and it’s chromatin target (H3K27me3) to determine if EZH2 can improve the prediction of cancer recurrence and progression. Currently, we have limited treatments for patients with non-muscle invasive bladder cancer. We will investigate the role of EZH2 by gene-targeting in mice to determine if loss of EZH2 is sufficient to block progression to muscle-invasion in a mouse model of bladder cancer. Finally, we will deliver the pharmaceutical inhibitor of EZH2, GSK126, to determine if this drug can block the progression of bladder cancer in an orthotopic bladder cancer model. The combined research will help all patients with bladder cancer, but particularly Veterans. Bladder cancer develops due to a combinations of genetic mutations and carcinogen exposures. Often, Veterans are unknowingly exposed to these carcinogens or have a disproportionately exposure to smoking tobacco. Cancer of the urinary tract is third among malignancies in the Veterans Affairs Cancer registry comprising 7.1% of all cancer diagnoses. If we are able to demonstrate a response of bladder tumors to the EZH2 inhibitor, this would provide pre-clinical data to support a phase I trial in patients- which Dr. Meeks could initiate within the year at both Northwestern and the Jesse Brown VA. Broadly, this work would have a significant impact on the field of cancer research by providing evidence that histone modification is a driver rather than a by-stander in the development of cancer. While mutations in histone modification genes are common in the cancer genome atlas of multiple tumors, their functional role in cancer has not been described. This research will fill that gap and provide evidence for a histone modifying enzyme as an oncogene in bladder cancer.