Grant: Operating Grant

Castration is the current treatment for advanced prostate cancer that involves the reduction of the patients' levels of testosterone (androgen). Unfortunately, castration therapies are not curative and eventually the disease will return in a form that is resistant to reduced levels of testosterone (called castration resistant disease). Two new reasons identified for castration resistance are: 1) synthesis of androgens directly by the tumor, and 2) generation of androgen receptor splice variants that act without needing androgens to activate the receptor. Thus, even though levels of androgen are decreased in the blood of castrated patients, the tumor still activates its androgen receptor by either synthesis of androgen by the tumor, or by making androgen receptor splice variants that work without androgen. Once the disease is castration resistant, the survival time is approximately two years before the patient will succumb to his disease. Currently no therapies increase survival by more than a few months for patients with castration resistant disease. To develop new therapies, a target must be known to create drugs that will bind to it. A drug that binds to the N-terminal domain of the androgen receptor would block both above mechanisms of resistance to current therapies. No current therapies target the N-terminal domain. Hence, we propose to identify small molecules (drugs) that bind to this target and test their feasibility for clinical development for the treatment of patients with advanced prostate cancer. We envision that upon conclusion of these studies, we will have identified important small molecules that can be used to develop new drugs that will delay or prevent lethal prostate cancer. Once a small molecule is found, usually it takes about 4-5 years to get into clinical trials depending on the ease of selection of a clinical candidate. This means that this proposed research has potential to impact the disease in a relatively short period of time.