Direct Targeting of the FKBP52 Cochaperone for the Treatment of Castration-Resistant Prostate Cancer

Prostate cancer affects one in seven men in the United States. In approximately one-third of diagnosed cases, the disease spreads and invades other tissues (metastasizes) to become life-threatening. Since prostate cancer requires male hormones, androgens, to grow and survive, the metastatic form of the disease has been treated with so-called androgen deprivation therapies, actual or chemical castration to prevent the testes from supplying androgens, and use of androgen blockers called anti-androgens. Unfortunately, these treatments only delay the progression of the disease and the cancer invariably returns in a form that no longer responds to these therapies, also called castration-resistant prostate cancer. Additionally, quality of life is severely affected during these years, as the treatment results in unpleasant and often harmful side effects. In castration-resistant prostate cancer, the tumor cells continue to rely on androgen receptor activity, indicating that the androgen receptor constitutes a key therapeutic target throughout disease progression. Unfortunately, many castration-resistant prostate cancer patients exhibit resistance by yet unknown mechanisms to the second generation of therapeutic agents designed to block androgen receptor. Activity of androgen receptor requires a coordinated assembly of a diverse group of proteins called co-activators and co-chaperones. Inhibiting or blocking the function of these androgen receptor co-activators and co-chaperones renders the androgen receptor non-functional. Based on this rationale, we have pursued the therapeutic targeting of a novel co-chaperone protein known to be critical for androgen receptor signaling and androgen receptor-dependent prostate development in mice. We previously characterized this protein as an attractive target for prostate cancer treatment, and, in this project, we propose to develop and characterize drugs that inhibit this novel target for the treatment of both early-stage and castration-resistant prostate cancer. The novel drugs that are developed as a result of this project are anticipated to offer both the positive properties of the anti-androgen drugs and, through the unique mechanism of action, prevent the undesirable side effects associated with anti-androgen treatment. In addition, these novel therapies are expected to bypass mechanisms leading to disease resistance to therapy. In addition to the identification of novel drugs, we will also generate preclinical data in cellular and animal models of prostate cancer that will be required for attracting commercial interest with the long-term goal of moving these drugs to clinical trials. We propose that the unique mechanism of action of the drugs developed in this project will lead to more potent and effective drugs for the treatment of castration-resistant prostate cancer, thereby filling a major unmet need in prostate cancer therapy.