Article

Targeting the androgen receptor pathway in prostate cancer.

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Current Opinion in Pharmacology (Impact Factor: 4.23). 09/2008; 8(4):440-8. DOI: 10.1016/j.coph.2008.07.005
Source: PubMed

ABSTRACT When prostate cancers progress following androgen depletion therapy, there are currently few treatment options with only one, docetaxel, that has been shown to prolong life. Recent work has shown that castration-resistant prostate cancers (CRPCs) continue to depend on androgen receptor (AR) signaling which is reactivated despite low serum androgen levels. Currently available AR-targeted therapy, including GnRH agonists and antiandrogens, cannot completely shut down AR signaling. Several mechanisms that enhance AR signaling in an androgen-depleted environment have been elucidated. These include AR mutations that allow activation by low androgen levels or by other endogenous steroids, AR overexpression, increased local intracrine synthesis of androgens, and upregulation of tyrosine kinase pathways. This has led to the development of a number of novel agents targeting the AR signaling pathway, including more effective antiandrogens, inhibitors of CYP17, an enzyme required for androgen synthesis, inhibitors of 5alpha-reductase, inhibitors of HSP90 which protects AR from degradation, inhibitors of histone deacetylases which is required for optimal AR-mediated transcription, as well as inhibitors of tyrosine kinase inhibitors. Many of these strategies are currently being tested in clinical trials in CRPC.

Download full-text

Full-text

Available from: Howard I Scher, Oct 08, 2014
0 Followers
 · 
95 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The first-line management of metastatic prostate cancer is hormonal therapy. However, resistance to this treatment will emerge within an average of 24 months. Our purpose was to determine the course of metastatic prostate cancer under treatment. A total of 56 patients who were diagnosed with metastatic prostate cancer were enrolled. As initial management, 3 kinds of hormonal therapy consisting of bilateral orchiectomy (BSO) alone, BSO + anti-androgene (AA) and LH-RH + AA were applied. The patients were followed until the emergence of hormone resistance. Serum PSA levels at the time of first diagnosis, post-treatment nadir PSA levels, time to nadir PSA, time to hormonal resistance and PSA levels at hormonal resistance were assessed, retrospectively. The localization and number of metastases and the survival term from the beginning of the emergence of hormone resistance until death were investigated No significant differences could be established between the groups. The mean time to reach hormone refractory status was 30.3 months for the whole study group. The average term of survival was 42.7 months for the whole group. Distance metastases were found in 8 patients during follow-up. There were no statistical differences between the groups in terms of treatment modalities applied for metastatic prostate cancer. Patients with androgen independent prostate cancer demonstrated progression despite chemical or surgical castration, and had poor prognosis. Initial hormonal therapy failed after an average of 2 years in metastatic prostate cancer.
    SpringerPlus 01/2015; 3. DOI:10.1186/2193-1801-3-725
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The prostate is an accessory sex gland of the male reproductive system, which produces alkaline prostatic fluid, capable of ensuring the spermatic viability to fertilize eggs within the female reproductive system. Functionally, the prostate is under the control of androgens, such as testosterone and dihydrotestosterone (DHT), and these hormones play a key role in the maintenance of sexual behavior and male reproduction. In prostatic microenvironment, the androgens may directly orchestrate its secretory activity and coordinate events that maintain its morphological integrity. It is noteworthy a dual role of androgens regulating both proliferation and apoptosis of the epithelial cell, suggesting the androgens
    Androgen Receptors: Structural Biology, Genetics and Molecular Defects, 1 edited by Silvio Socorro, 01/2014: chapter ANDROGEN RECEPTOR SIGNALING IN PROSTATE CANCER: GENETIC AND MOLECULAR ASPECTS: pages 83-106; NOVA SCIENCE PUBLISHERS., ISBN: 978-1-62948-693-2
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Androgen ablation therapy is the most common treatment for advanced prostate cancer (PCa), but most patients will develop castration-resistant prostate cancer (CRPC), which has no cure. CRPC is androgen-depletion resistant but androgen receptor (AR) dependent. AR is a nuclear receptor whose transcriptional activity is regulated by hormone binding to the ligand-binding domain (LBD). Constitutively active AR splice variants that lack LBDs often are expressed in CRPC. The expression of these variants indicates that methods to inhibit AR activity that do not rely on inactivating the LBD are needed. Heat shock protein 90 (Hsp90), a potential therapeutic target in PCa, is an AR chaperone crucial for proper folding, hormone binding and transcriptional activity of AR. We generated LNCaP cell lines with regulated expression of the AR-V7 variant as well as a cell line expressing artificially truncated AR (termed AR-NTD) to characterize splice variant function. Using an Hsp90 inhibitor, Geldanamycin (GA), and an AR-Hsp90-FKBP52 specific inhibitor, MJC13, we sought to determine if the AR variants also require Hsp90 and associated co-chaperone, FKBP52, for their activity. GA inhibits AR transcriptional activity but has little effect on AR-V7 activity. Moreover, GA decreases the stability of AR protein, with no effect on AR-V7 levels. Full-length AR activity is strongly inhibited by MJC13 while AR-V7 is unaffected. Thus, the variants are resistant to inhibitors of the Hsp90-AR heterocomplex. Although Hsp90 inhibitors will continue to inhibit growth promoting kinases and signaling through activated full-length AR in CRPC, AR signaling through variants will be retained.
    Steroids 02/2013; DOI:10.1016/j.steroids.2012.12.013 · 2.72 Impact Factor

Similar Publications