Hormone therapies block androgen production and/or androgen receptor (AR) function, leading to a period of clinical regression varying from months to more than 6 years among patients treated for metastatic prostate cancer. Because restored AR signaling is the key determinant of castration-resistant prostate cancer (CRPC), suppression of AR signaling has been the common goal and efficacy marker of nearly all existing CRPC therapies. For example, the Phase III trial for abiraterone acetate showed significant overall survival benefit to CRPC patients in the post-docetaxel setting. While this Food and Drug Administration-approved CRPC therapy has the potential to improve the outcome of men with CRPC, the majority of patients progress with a rising PSA (prostate-specific antigen), suggesting a return of AR signaling. There is, therefore, an urgent need to dissect resistance to this and other novel CRPC agents currently in various stages of clinical development. The proposed studies in this application represent our efforts to develop molecular indicators of CRPC that may be utilized in the clinic to support personalized treatment of CRPC patients and to accelerate successful clinical development of novel CRPC therapies.

Our efforts are motivated by recent research advances in androgen receptor variants (AR-Vs) that are resistant to castration therapies. We view these new discoveries as opportunities that have yet to be capitalized upon to address the unmet need of developing indicators of castration resistance. We are now equipped with the knowledge that AR-Vs are both structurally and functionally distinguishable from the full-length AR (AR-FL), which is the canonical target in various endocrine approaches for advanced prostate cancer. The tools and methods we have developed so far will allow us to fully distinguish and dissect the levels of AR-FL and AR-Vs as well as their functions in CRPC.

Given these opportunities, we have assembled a team of clinicians and scientists to discover and develop molecular indicators of CRPC by targeting the AR-Vs and by dissecting the complexities of AR signaling in CRPC. Our first goal is to find all AR-Vs in clinical CRPC specimens through cutting-edge technology recently developed and validated in the Principal Investigator's lab. The studies will help us to develop a "signature" of AR-Vs that defines CRPC and to enrich the pipeline of candidate indicators of CRPC that will be further developed. Our second goal is to establish the proof of principle that AR-V levels detected prior to the initiation of hormone therapies may be used to predict CRPC progression; we will do so by evaluating a cohort of patients presenting with metastatic prostate cancer and immediately treated by hormone therapies. The proposed studies will also dissect the relative roles of AR-FL and AR-Vs in CRPC because we designed the studies to evaluate both of them.

If we are successful (in developing molecular indicators of CRPC and establishing the proof of principle that baseline AR-V levels may explain resistance to drugs targeting AR-FL), this project will have a far-reaching impact on the management of men with advanced prostate cancer and particularly men with CRPC. A number of new CRPC drug candidates are currently being evaluated at various stages of clinical development. Overall, these new treatments provide men with CRPC unprecedented hope that this lethal disease may be controlled for a prolonged period of time. Yet there is an unmet need on the biomarker front. As a result, clinicians cannot explain why some CRPC patients benefit from prolonged remission whereas others experience progression shortly after treatment. Development of molecular indicators of drug resistance will help to guide clinical decisions related to the timing or type of treatments given to CRPC patients and help to establish objective treatment criteria as well as surrogate endpoints that may lead to shortened clinical trials. Outside the scope of this application, we have initiated collaborative efforts to address assay development in a more clinically relevant setting that will involve blood-based RNA and DNA assays. Given the existing collaborations with clinicians directly involved in clinical development of abiraterone and other CRPC therapies, we expect a high likelihood of integrating study findings into existing clinical trials (to embed a biomarker question in prospective trials) at the end of the 3-year project period.