Castration-resistant prostate cancer: Targeting androgen metabolic pathways in recurrent disease

Emerging evidence suggests that despite testicular androgen ablation, residual androgens, likely of adrenal—though potentially of prostatic—origin, play a critical role in the progression of prostate cancer to recurrent “castration-resistant” disease. Thus, a reassessment of the concept of total androgen deprivation is warranted. Current treatment strategies may not only lack optimal efficacy, but may actually contribute to the selection of neoplastic clones adapted to exist and proliferate in a low (but not zero) androgen environment. Moreover, the adequacy of androgen receptor (AR) pathway inhibition cannot be surmised from serum or plasma androgen levels, but must be ascertained at the tissue and molecular level prior to drawing conclusions regarding clinical efficacy or failure. Recent studies by our group and others indicate that prostate cancers undergo an adaptive response to castration that is associated with the up-regulation of transcripts encoding enzymes involved in the biosynthesis of androgens. Targeting these metabolic enzymes either individually or using combinations of agents to inhibit testicular, adrenal, and intracrine sources may provide enhanced clinical responses in the setting of both localized and metastatic disease.