Emerging evidence from basic, translational and clinical studies has shown the significance of the HGF/c-Met signaling pathway in prostate cancer progression and CRPC development. The hepatocyte growth factor (HGF) plays a critical role through its receptor c-Met in the regulation of cell growth, cell motility, morphogenesis, and angiogenesis. The HGF and c-Met axis is a significant contributor to epithelial-stromal interactions, which directly contributes to prostate cancer progression and metastasis. Up-regulation of c-Met expression has been observed in most metastatic prostate cancer lesions. Interestingly, despite the high incidence of c-Met expression in prostate cancer, c-Met amplification was only observed in about 10% of metastatic prostate cancers, suggesting other regulatory mechanisms underlying aberrant expression of c-Met. The benchwork done in my lab has demonstrated a novel role of AR as a transcriptional repressor in c-Met expression in prostate cancer cells. Our finding not only elucidates an aberrant regulation of c-Met expression in prostate cancer cells, but also implicates a novel mechanism by which current androgen ablation therapy induces CRPC development. While current androgen ablation therapy suppresses activation of the growth promoting gene expression induced by the AR, it also attenuates AR repression of c-Met expression, resulting in an increase of c-Met in tumor cells. Since overexpression of c-Met directly correlates with more aggressive prostate tumor phenotypes, adding c-Met inhibitors to current androgen ablation monotherapy may improve clinical outcomes, and delay and prevent CRPC development. Thus, in this amended R01 application, we propose three unique but integrated specific aims to directly test our central hypothesis: Inhibition of androgen action through current androgen ablation therapy increases c-Met expression thereby promoting tumor invasion, hormone refractoriness, and metastasis, and combined inhibition of AR and c-Met oncogenic pathways can prevent or delay CRPC development. This timely study seeks to break new ground and change current paradigms for the treatment of advanced prostate cancer. Data generated from this study should provide critical and necessary scientific evidence for clinical intervention of lethal CRPC to improve survival rates for hundreds of thousands of men.