From pathogenesis to prevention of castration resistant prostate cancer.

Background: Significant progress in understanding the molecular basis of castration resistant prostate cancer (CRPCa) has been achieved in recent years. Despite this progress, CRPCa still remains a lethal disease. Early detection and prevention of CRPCa may provide a new strategy to improve survival of patients diagnosed with PCa at risk to fail standard androgen deprivation therapy (ADT).

Methods: Herein, we review pathogenetic mechanisms implicated in PCa progression toward castration resistant disease that are detectable in hormone naive PCa to define relevant therapeutic targets for prevention.

Results: Upregulation of androgen receptor (AR) expression has been recognized a major determinant for the development of CRPCa. This hypersensitive pathway is further boosted by the increase of intratumoral androgen synthesis. AR mutants bind promiscuous steroids, and may convert AR antagonists to agonists. Various non-hormonal growth factor receptors transactivate the AR, even in absence of androgens (outlaw pathway). Finally, PCa cells can bypass the AR through various mechanisms, including BCL-2, COX-2, neuroendocrine differentiation. Most of these pathogenetic factors involved in the development of CRPCa are detectable in hormone naive PCa tissue even at the time of initial diagnosis, and could be targeted by drugs currently available.

Conclusions: CRPCa is the end-stage of a multifactorial and heterogeneous disease process. Pathogenetic factors responsible for the development of the CRPCa phenotype are detectable in the patient's PCa tissue long before the clinical onset of the disease. This approach provides opportunity for early detection and prevention by targeting pathways relevant for the individual disease process.