New strategies in metastatic prostate cancer: targeting the androgen receptor signaling pathway

Abstract

Recent data report that abiraterone acetate, a specific inhibitor of CYP17 that is key to androgen and estrogen synthesis, improves survival in metastatic castration-resistant prostate cancer (CRPC), confirming the continued dependency of CRPC on the androgen receptor (AR) signaling pathway. MDV3100 is a novel antagonist of AR that is also in phase III clinical trials. In addition, several other agents targeting the AR axis are undergoing evaluation in early clinical studies. CRPC patients progress on these therapies with an increasing prostate specific antigen (PSA), suggesting that repeated therapeutic interventions targeting the AR signaling axis could induce secondary responses and achieve prolonged clinical benefit for a subgroup of patients. These exciting results are good news for patients but introduce a number of treatment paradigm dilemmas for physicians. Clinical studies evaluating the ideal sequence of administration of these new agents, best timing for initiation, combination strategies, discontinuation beyond progression and after commencement of subsequent therapies, and coordination with other treatments have not been done. Predictive biomarkers could allow patient selection for a specific treatment, but in their absence, most physicians will rely on a trial of treatment with a preferred agent and substitute for an alternative therapy on objective progression. Current data suggest that the response rate to drugs targeting the AR ligand-binding domain decreases with each treatment, but we hypothesize that a significant proportion of CRPC remains dependent on the AR axis and, therefore, novel strategies for disrupting AR signaling merit evaluation.

Figure 1. Strategies for therapeutically targeting the androgen receptor (AR)

The hypothalamus-pituitary-gonadal axis controls androgen synthesis as part of a negative feedback loop. Luteinising hormone (LH) is released from the pituitary following stimulation by luteinizing hormone releasing hormone (LHRH) and stimulates testicular androgen production while adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary stimulates the adrenal production. Androgens or alternative ligands bind to wild-type or mutant AR, causing dissociation from heat shock proteins (HSP) and translocation of the AR to the nucleus. The AR binds to androgen response elements on androgen responsive genes including TMPRSS2:ERG and PSA and coregulatory proteins are recruited for transcriptional activation. The 3 main structural components of the AR, the N-terminal domain (NTD), DNA-binding domain (DBD) and the ligand-binding domain (LBD) are shown separately. Strategies with marketing approval or in late stages of clinical development involve targeting of the LBD or androgens; other potential ligands exist. Microtubules may also be essential to AR function and could be disrupted with taxanes. More novel strategies involve targeting of the NTD or chaperone proteins.