Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer

Abstract

Clinical data and models of human disease indicate that androgen receptor (AR) activity is essential for prostate cancer development, growth, and progression. The dependence of prostatic adenocarcinoma on AR signaling at all stages of disease has thereby been exploited in the treatment of disseminated tumors, for which ablation of AR function is the goal of first-line therapy. Although these strategies are initially effective, recurrent tumors arise with restored AR activity, and no durable treatment has yet been identified to combat this stage of disease. New insights into AR regulation and the mechanisms underlying resurgent AR activity have provided fertile ground for the development of novel strategies to more effectively inhibit receptor activity and prolong the transition to therapeutic failure.

Figure 1. Androgen receptor re-activation in prostate cancer progression

Structure: The androgen receptor (AR) consists of a 3 domains that are highly conserved among the nuclear receptors (the DNA binding domain, DBD; a hinge region; and a C-terminal ligand binding domain, LBD), and unique N-terminal domain, which contains the principle transactivation domain (TAD). Regulation: Ligand (represented by circles, testosterone, T or dihydrotestosterone, DHT) binding induces homodimerization, intramolecular interaction of the N- and C-termini, and rapid nuclear translocation. Active homodimers bind DNA at AREs within the regulatory regions of target genes, recruits coactivators, and induces a gene expression program that includes activation of Prostate Specific Antigen (PSA). Current therapies: The AR C-terminal domain is targeted clinically by the use of GnRH agonists to deplete androgen systhesis (Androgen Depletion) and direct AR antagonists (represented by triangles) that actively inhibit AR activity and foster corepressor recruitment. Re-activation: AR is reactivated during disease progression by the mechanisms indicated, thus leading to restored androgen synthesis, sensitization to low level or alternate ligands, and/or androgen independent AR activation. These events result in restored AR signaling (“Biochemical Progression”) and promote recurrent, castration resistant tumor formation (CRPC).

Figure 2. New opportunities for durable AR regulation

Ligand depletion strategies: In addition to the currently used GnRH agonists, GnRH antagonists have been developed, which eliminate testosterone surges. Abiraterone provides an advantage through an ability to suppress both testicular and adrenal androgen synthesis, whereas VN/124-01 can both suppress CYP17 activity and also reduce AR levels. AR destabilization: Mechanisms to destabilize AR could be potentially achieved through HSP90 inhibitors or inhibitors of HDAC-HSP90 association. Alternatively, peptides have been used to disrupt AR N-C terminal interaction that could reduce AR association with chromatin, in addition to peptides derived from AR corepressors. Direct AR antagonists: The next generation AR antagonist MDV3100 is in clinical trial, and precludes both AR-DNA association and AR nuclear accumulation.