Molecular States Underlying Androgen Receptor Activation: A Framework for Therapeutics Targeting Androgen Signaling in Prostate Cancer

Abstract

“You can observe a lot just by watching.” —Yogi Berra The androgen receptor (AR) is a resilient foe. Since the landmark studies of Huggins et al demonstrated the sensitivity of prostate cancer to androgenic hormones, androgen deprivation therapy has been the most widely used and effective treatment for metastatic disease. Although initial response rates exceed 90%, the eventual emergence of castration-resistant prostate cancer (CRPC) is nearly universal, and it represents a disease state that is usually fatal. However, a remarkable and extremely important aspect of CRPC is the near-universal reactivation of AR signaling, a finding readily substantiated through measurements of high serum concentrations prostatespecific antigen (PSA), a gene directly and exclusively regulated by the AR. Several studies have documented that most, and potentially all, genes known to be under AR transcriptional control in prostate cancer cells are re-expressed in CRPC tumors. In this context, the AR may be the earliest known example of a lineage oncogene—a master regulator to which neoplastic cells derived from prostate epithelium are addicted. AR engagement by androgenic ligands such as testosterone and dihydrotestosterone motivate AR migration from the cytoplasm to the nucleus, where AR target genes are recognized and activated through DNA binding to locations specified by nucleotide sequence and chromatin accessibility. The observation that AR-regulated genes are active in CRPC—despite undetectable levels of testosterone in blood—has prompted efforts to identify processes driving AR function in the castrate environment. Such alternative mechanisms of AR activation could represent targets for therapeutic inhibition. A key question that should influence further investment in obstructing the AR program in CRPC is whether the AR is continuing to provide the growth and survival signals for these tumors, or if the AR program is simply baggage carried along by other oncogenic drivers. Compelling evidence indicates the former is likely to be true. For example, experiments abolishing the AR itself in androgenrefractory prostate cancer cells in vitro effectively suppressed proliferation. CRPC tumors proliferating in castrate mice consistently regress after the targeted elimination of AR expression. Finally, clinical studies of secondary and tertiary methods to inhibit AR signaling in CRPC usually result in PSA and clinical responses, although they are generally of relatively short duration. Newer agents targeting androgen biosynthesis or blocking AR activation carry on this tendency. Together, these laboratory and clinical observations emphasize the continued relevance of the AR pathway as a key therapeutic node in the vast majority of patients with advanced CRPC. Unfortunately, over the past several decades, efforts to target AR signaling have blown hot and cold, with irrational exuberance followed by neglect. Insightful studies by Geller et al in the 1970s demonstrated that androgen levels within prostate cancers far exceeded concentrations found in castrate men, a finding that ushered in the era of combined androgen blockade (CAB) with steroidal and nonsteroidal androgen receptor antagonists. Despite many trials of CAB, the therapeutic advantage remains highly debated. Initial studies using either surgical or medical castration in conjunction with an antiandrogen suggested significant improvements in survival compared with historical controls. However, the benefits measured in subsequent randomized trials were not encouraging, although metaanalyses have consistently shown a statistically significant improvement in 5-year survival, on the order of 5%, in favor of CAB. Although certainly less impressive than anticipated, the trials of these early antiandrogens did not refute the hypothesis that AR is still a key driver in CRPC because of one key observation: Patients for whom these drugs failed experienced progression with a rising PSA, indicating the AR pathway remained active. Determining how the AR remained engaged awaited detailed molecular studies that identified mechanisms underlying the limited effectiveness of these AR antagonists and led to the next generation of AR inhibitors, such as MDV3100, with enhanced binding affinities and lacking agonist properties. To provide a framework for the clinical application of new agents designed to suppress androgen signaling, it is useful to consider the molecular endocrinology that underlies the maintenance of AR activity. On the basis of current knowledge of prostate cancer molecular biology, at least four discrete cellular states of prostate cancer can be defined, based solely on the status of AR program activity and the mechanism by which it is activated. Of clinical relevance, the cellular states are dynamic and evolve either through adaptation or genomic events, and each molecular state is also associated with a specific therapeutic node that generally requires effective inhibition—and JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 30 NUMBER 6 FEBRUARY 2