Current treatment for advanced prostate cancer involves the reduction of the patients' levels of testosterone (an androgen). This reduction of testosterone can be achieved by either chemical (drugs) or surgical (orchiectomy) approaches to "castrate" the patient. Unfortunately, these forms of castration therapy are not curative, and eventually the disease will return in a form that is resistant to reduced levels of testosterone (called castrate-resistant). Two new reasons that have been identified for castration resistance are: (1) Synthesis of androgens directly by the tumor, and (2) generation of androgen receptor variants that act without needing androgens to activate the receptor. Thus, no matter how much the levels of androgen are decreased in the blood by castration, the tumor still activates its androgen receptor in the former case (synthesis of androgen by the tumor), and even if tumor androgens are blocked, the androgen receptor remains activated in the latter situation (generation of androgen receptor variants).

Once the disease is castrate-resistant, the survival time is approximately two years before the patient will succumb to his disease. There are not any effective therapies currently available for these patients. To develop new therapies, a target must be known, this target is the androgen receptor. We have targeted a unique region, the N-terminus, of the androgen receptor for drug development. This target was supported by pre-existing knowledge that testosterone (an androgen) stimulates the growth of "normal" prostate cells by activating androgen receptors located in the cell. The activation of the androgen receptor is also linked to the growth of prostate cancer cells and is the basis for reducing levels of testosterone for patients with prostate cancer. However, it has been proposed that in castrated patients, the tumor itself may produce androgen at levels sufficient to fuel the cancer by activating the androgen receptor. Work in our laboratory and others have yielded results verifying the importance of activating the androgen receptor in castrated patients as a potential underlying cause for lethal disease. A unique region on the androgen receptor, called the N-terminus, appears to be responsible for its activation and provides a novel therapeutic target. Work has validated that blocking the N-terminus of the androgen receptor prevents the growth of prostate cancer in animals. We have identified a drug called EPI-001 that is the first drug works on the N-terminus of the androgen receptor. Together, this data provides the rationale for the studies proposed, which include testing if EPI-001 prevents or delays the progression of prostate cancer to the castrate-resistant lethal stage. IND-directed preclinical studies are currently ongoing with EPI-001 with the expectation of clinical trials starting within 2 years. The studies proposed here will reveal the feasibility of EPI-001 (and the role of the N-terminus of the androgen receptor) in the growth of castrate-resistant prostate cancer and help define the direction of EPI-001 clinical trials currently under development.