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Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions.

ABSTRACT: Since the year 2000, tremendous progress has been made in the understanding of castration-resistant prostate cancer (crpc), a disease state now recognized to retain androgen receptor (ar)-dependency in most cases. That understanding led to the rational design of novel therapeutic agents targeting hormonal pathways in metastatic crpc. Two new drugs-the CYP17 inhibitor abiraterone acetate and the potent ar antagonist enzalutamide-were recently shown to prolong overall survival after chemotherapy treatment in patients with metastatic disease, with the former agent also demonstrating impressive activity in the pre-chemotherapy setting. Other new drugs targeting the ar-as well as drugs targeting heat shock proteins that protect cytoplasmic ar from degradation-are currently undergoing clinical development.This review briefly describes the molecular mechanisms underlying castration resistance and hormonal dependence in prostate tumours and summarizes the current ongoing and completed clinical trials that are targeting hormonal pathways in metastatic crpc. Potential mechanisms of resistance to these novel hormonal agents are reviewed. Finally, future research directions, including questions about drug sequencing and combination, are discussed.

SUBMITTER: Leibowitz-Amit R

PROVIDER: S-EPMC3553559 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions.

Leibowitz-Amit R R Joshua A M AM

Current oncology (Toronto, Ont.) 20121201 Suppl 3

Since the year 2000, tremendous progress has been made in the understanding of castration-resistant prostate cancer (crpc), a disease state now recognized to retain androgen receptor (ar)-dependency in most cases. That understanding led to the rational design of novel therapeutic agents targeting hormonal pathways in metastatic crpc. Two new drugs-the CYP17 inhibitor abiraterone acetate and the potent ar antagonist enzalutamide-were recently shown to prolong overall survival after chemotherapy t ...[more]

PMID: 23355790

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Project description:Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor's androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat castration-resistant prostate cancer.

Dataset Information

Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions.

Publications

Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions.

Similar Datasets

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