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.