Treatment of human prostate cancer has relied on androgen deprivation therapy (ADT) by way of physical and chemical castration. Unfortunately, ADT often leads to castration resistant prostate cancer (CRPC). It is likely that combinatorial treatment with multiple AR pathway-directed therapies will eliminate AR signaling, but is unlikely to be a curative therapy in most patients. Ultimately, androgen receptor-independent prostate cancer (APIPC) is likely to emerge and become a dominant clinical problem. The research plan that comprises this training application is ambitious, but addresses a very important basic and clinical problem. Each of the Aims has the potential to break new ground including the development of key model systems, the identification of new APIPC targets, and developing an understanding of key mechanistic drivers of prostate cancer progression. Importantly, we have shown feasibility for each aim. I will have substantial support from members of the Nelson laboratory and collaborators. The key reagents are in-hand and I have developed experience working with the cell lines, constructs, high-throughput screening data, and cell biology assays. The training I will receive, and the data that I will produce will provide a strong foundation for n independent research career.
The treatment of human prostate cancer has relied on androgen deprivation therapy (ADT) by way of physical and chemical castration. Unfortunately; ADT often leads to castration resistant prostate cancer (CRPC) and ultimately androgen receptor-independent prostate cancer (ARIPC); an aggressive and usually fatal cancer state. Therefore; the successful treatment of human prostate cancer requires additional preclinical research to gain a greater understanding of prostate cancer development and progression. By developing new model systems; I aim to identify key factors that promote the progression of androgen-dependent prostate cancer to androgen-independent prostate cancer (CRPC) and ARIPC. These factors will likely represent signaling pathways that are used by prostate cancer cells during the progression to advanced CRPC and ARIPC to bypass ADT. These factors also represent likely therapeutic targets that can be exploited by clinicians to successfully treat patients suffering from advanced prostate cancer and metastatic disease associated with prostate cancer. This proposal is relevant to advanced prostate cancer as well as general cancer biology as it is likely that factors identified in this study that promote the progression o human prostate cancer may have similar action/roles in other human cancers particularly those initially responsive to hormones; such as breast carcinoma.