Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials. 1. Introduction Prostate cancer is the most common noncutaneous malignancy and one of the common causes of cancer related deaths among men in the United States [1]. The majority of men are diagnosed with early stage disease. However, approximately a third will eventually develop metastatic disease. The cornerstone of treatment for advanced disease is medical castration by androgen deprivation therapy with a gonadotropin releasing hormone agonist (GnRH) or less commonly, surgical castration with orchiectomy. Despite initial responses, almost all patients will develop disease progression, a stage known as metastatic castration refractory prostate cancer (mCRPC). One of the reasons why prostate cancer continues to progress is the persistence of androgen receptor signaling, despite castrate level of androgens [2]. Additionally, there are androgen independent pathways responsible for prostate cancer progression. This paper summarizes the recent advancements in the development of therapies that target these molecular pathways in CRPC, with an emphasis on agents that are being evaluated in phase II or III clinical trials and those recently approved for the treatment of CRPC
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