Chen Y, Sawyers CL, Scher HI.. Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 8: 440-448

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Current Opinion in Pharmacology (Impact Factor: 4.6). 09/2008; 8(4):440-8. DOI: 10.1016/j.coph.2008.07.005
Source: PubMed


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.

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Available from: Howard I Scher, Oct 08, 2014
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    • "Most of the prostate cancers (PCa) are, at least at the beginning, endocrine-dependent tumors. Therefore, hormonal therapy is still a first-choice treatment (Chen et al. 2008). The first effects to hormonal treatment with medical or surgical castration are quite considerable, with rapid biochemical responses, as evaluated by declines in levels of the serum marker, prostatespecific antigen (PSA) (Di Lorenzo et al. 2010; Chi et al. 2009). "
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    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.
    Full-text · Article · Feb 2015 · SpringerPlus
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    • "The mechanism of AR protein stabilisation by the BCAS2–AR–HSP90 is an interesting subject for future investigation. There are several drugs targeting AR for prostate cancer therapy, such as the HSP90 inhibitor (Solit et al, 2002; Chen et al, 2008; Heath et al, 2008). BCAS2 can be a target for cancer therapy, because it is a diagnostic marker of prostate cancer (Figure 2). "
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    ABSTRACT: Background: We showed previously that breast carcinoma amplified sequence 2 (BCAS2) functions as a negative regulator of p53. We also found that BCAS2 is a potential AR-associated protein. AR is essential for the growth and survival of prostate carcinoma. Therefore we characterised the correlation between BCAS2 and AR. Methods: Protein interactions were examined by GST pull-down assay and co-immunoprecipitation. Clinical prostate cancer (PCa) specimens were evaluated by immunohistochemical assay. AR transcriptional activity and LNCaP cell growth were assessed by luciferase assay and MTT assay, respectively. Results: BCAS2 expression was significantly increased in PCa. BCAS2 stabilised AR protein through both hormone-dependent and -independent manners. There are at least two mechanisms for BCAS2-mediated AR protein upregulation: One is p53-dependent. The p53 is suppressed by BCAS2 that results in increasing AR mRNA and protein expression. The other is via p53-independent inhibition of proteasome degradation. As BCAS2 can form a complex with AR and HSP90, it may function with HSP90 to stabilise AR protein from being degraded by proteasome. Conclusions: In this study, we show that BCAS2 is a novel AR-interacting protein and characterise the correlation between BCAS2 and PCa. Thus we propose that BCAS2 could be a diagnostic marker and therapeutic target for PCa.
    Full-text · Article · Dec 2014 · British Journal of Cancer
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    • "Androgen signalling plays a pivotal role in PCa and increased AR expression is a common feature of both primary tumours and metastases, with a high AR profile in the latter correlating to larger tumour size [12]. The majority of CRPC tumours overexpress AR [13–15], and the AR gene is amplified in approximately a third of cases [16]. The resulting elevated levels of receptor allow cancer cells to be stimulated by low concentrations of androgen [17], which continue to be synthesised in CRPC [18], and afford protection from high-dose antiandrogen therapy, e.g. "
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    ABSTRACT: The androgen receptor (AR) is a widely expressed ligand-activated transcription factor which mediates androgen signalling by binding to androgen response elements (AREs) in normal tissue and prostate cancer (PCa). Within tumours, the amount of AR plays a crucial role in determining cell growth, resistance to therapy and progression to fatal castrate recurrent PCa in which prostate cells appear to become independent of androgenic steroids. Despite the pivotal role of the AR in male development and fertility and all stages of PCa development, the mechanisms governing AR expression remain poorly understood. In this work, we describe an active nonconsensus androgen response element (ARE) in the 5′ UTR of the human AR gene. The ARE represses transcription upon binding of activated AR, and this downregulation is relieved by disruption of the regulatory element through mutation. Also, multiple species comparison of the genomic region reveals that this ARE is specific to primates, leading to the conclusion that care must be exercised when elucidating the operation of the human AR in PCa based upon rodent promoter studies. Electronic supplementary material The online version of this article (doi:10.1007/s12672-014-0185-y) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2014
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