DESCRIPTION (provided by applicant): Prostate cancer (PCa) is a devastating disease that affects a large number of men. Androgen deprivation therapy (ADT) has been the central theme in the treatment of recurrent and advanced PCa for many decades, yet no patients were cured by this means. The development and progression of castration-resistant PCa (CRPC) remains a major treatment challenge because even the newly FDA-approved second-line ADT treatments (abiraterone and enzalutamide) provide limited survival benefits (3-6 months). Not only that CRPC is rapidly adapting to these therapies, but also CRPC (like other solid tumors) is heterogeneous and some tumors do not respond. A common assumption is that the persistence of androgen receptor (AR) signaling accounts for the failure of this intervention, and the prevailing clinical development is to achieve a complete blockade of AR signaling. However, AR regulates growth of PCa cells and also differentiation of prostate epithelium/cancer cells. Instead of promoting growth, supra physiological levels of testosterone (high-T) have actually been shown to inhibit growth of CRPC that failed traditional ADT in vitro, in vivo, and in patients We hypothesize that high-T alone and/or with dutasteride will inhibit abiraterone-resistant (AbiR) PCa, and re-sensitize the tumor to abiraterone (Abi) treatment. Our objective is to perform preclinical studies to investigate the efficacy of the high-T therapy using different AbiR CRPC LuCaP xenografts and to get insight into the mechanisms underlying high-T responsiveness and/or resistance. The proposed studies intend to fill a critical void in our understanding of the roles of supra-physiological AR signaling in CRPC. The information generated from these studies may substantially alter our views of treatments for CRPC.

PUBLIC HEALTH RELEVANCE: The development and progression of castration-resistant prostate cancer (CRPC) remains a major treatment challenge, and it is timely and important to develop new treatment modalities for CRPC, because even the newly FDA-approved second-line androgen-deprivation treatments (abiraterone and enzalutamide) provide limited survival benefits for 3-6 months. Non disputably, androgen has been shown to stimulate prostate tumor growth; however, a few recent studies has shown that high-dose testosterone (high-T) actually inhibited the growth of CRPC and is safe for patients with CRPC that failed traditional androgen-deprivation therapy. High-T treatment, if proven effective in this proposed study, will not only provide survival benefits but also improve the quality of life of patients with end-stage AbiR CRPC.