Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion

Abstract

Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data support its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress androgen levels and androgen-receptor-mediated effects at the tissue level. Advances in the understanding of mechanisms that contribute to castration-resistant prostate cancer are leading to rationally designed therapies targeting androgen metabolism and the androgen receptor. The results of large trials investigating the optimization of primary androgen deprivation therapy, including evaluation of intermittent androgen suppression and phase III studies of novel androgen synthesis inhibitors, such as abiraterone acetate, are eagerly awaited.

Figure 1. Androgen action

Testosterone circulates in the blood bound to albumin (not shown) and SHBG, and exchanges with free testosterone. Free testosterone enters prostate cells and is converted to DHT by the enzyme 5[alpha]-reductase. Binding of DHT to the AR induces dissociation from HSPs and receptor phosphorylation. The AR dimerizes and can bind to androgen-response elements in the promoter regions of target genes. Coactivators (such as ARA70) and corepressors (not shown) also bind the AR complex, facilitating or preventing, respectively, its interaction with the GTA. Activation (or repression) of target genes leads to biological responses including growth, survival and the production of PSA. Potential transcription-independent actions of androgens are not shown. Reproduced, with permission, from Feldman BJ and Feldman D (2001) Nat Rev Cancer 1: 34–45 © Macmillan Publishers Ltd. All rights reserved. Abbreviations: AR, androgen receptor; ARA70, androgen receptor associated protein 70; DHT, dihydrotestosterone; GTA, general transcription activation; HSP, heat-shock protein; SHBG, sex-hormone-binding globulin.

Figure 2. Mechanisms of castration resistance in prostate cancer

This Figure provides an overview of mechanisms demonstrated or hypothesized to be involved in the development of castration resistance in prostate cancer, divided into ligand-dependent and ligand-independent mechanisms. (1) Tissue and tumoral steroidogenesis contribute to synthesis of testosterone and DHT, and might lead to persistence of tissue-level androgen despite castration. (2) Mutations in the AR allow activation by alternate ligands or increased affinity for androgens. (3) Amplification increases AR abundance. (4) Ligand-independent activation of AR through ligand-independent modifications or cross-talk with other pathways, including phosphorylation of AR leading to hypersensitization and increased nuclear translocation. (5) Change in the balance of coactivators and corepressors augment AR activity. (6) Bypass pathways functioning independently of AR activity through upregulation of antiapoptotic molecules, such as Bcl-2. (7) Stem cells continuously produce both androgen-sensitive and castration-resistant clones. Abbreviations: AKT, akt serine/threonine kinase; AND, other androgenic steroidal precursors; AR, androgen receptor; DHEA, dihydroepiandrosterone; DHT, dihydrotestosterone; ERK, extracellular signal-regulated kinase; P, phosphorylated residues; PI3K, phosphoinositide 3-kinase; PTEN, phoshatase and tensin homolog.