Anti-androgens and androgen-depleting therapies in prostate cancer: New agents for an established target

Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
The Lancet Oncology (Impact Factor: 24.69). 10/2009; 10(10):981-91. DOI: 10.1016/S1470-2045(09)70229-3
Source: PubMed


Activation of the androgen receptor is crucial for prostate cancer growth at all points of the illness. Current therapies targeting the androgen receptor, including androgen-depletion approaches and anti-androgens, do not completely inhibit the receptor activity. Prostate cancer cells develop resistance to castration by acquiring changes that include androgen-receptor overexpression and overexpression of enzymes involved in androgen biosynthesis, which result in reactivation of the receptor. Based on an understanding of these resistance mechanisms and androgen biosynthesis pathways, new anti-androgens and androgen-depleting agents have been developed. Notably, promising activity has been shown in early phase trials by MDV3100, a new anti-androgen designed for activity in prostate cancer model systems with overexpressed androgen receptor, and by abiraterone acetate, a CYP17A inhibitor that blocks steroid biosynthesis in the adrenal gland and possibly within the tumour. Both agents are undergoing phase 3 testing. Here, we review the basic science and clinical development of these and other agents.

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Available from: Howard I Scher, Oct 08, 2014
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    • "Androgen receptor signaling has been shown to regulate the proliferation of PCa cells even in the advanced phase of the disease. Progression to the castration-resistant state depends on the AR (even after androgen deprivation therapy) because the receptor functions through its mutated form and/or is overexpressed (Chen et al., 2009). Therefore, the AR still remains a key driver of castration-resistant prostate cancer. "
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    ABSTRACT: There has been a resurgence of interest in the development of androgen receptor (AR) inhibitors with alternative modes of action to overcome the development of resistance to current therapies. We demonstrated previously that one promising strategy for combatting mutation-driven drug resistance is to target the Binding Function 3 (BF3) pocket of the receptor. Here we report the development of a potent BF3 inhibitor, 3-(2,3-dihydro-1H-indol-2-yl)-1H-indole, which demonstrates excellent antiandrogen potency and anti-PSA activity and abrogates the androgen-induced proliferation of androgen-sensitive (LNCaP) and enzalutamide-resistant (MR49F) PCa cell lines. Moreover, this compound effectively reduces the expression of AR-dependent genes in PCa cells and effectively inhibits tumor growth in vivo in both LNCaP and MR49F xenograft models. These findings provide evidence that targeting the AR BF3 pocket represents a viable therapeutic approach to treat patients with advanced and/or resistant prostate cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.
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    • "This necessitates careful monitoring of adverse events and drug interactions. The responses observed after treatment with ketoconazole lead to the investigation of stronger and more selective CYP 17 inhibitors with a more favorable toxicity profile than ketoconazole [25]. "
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    ABSTRACT: Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. Additionally, prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC. However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral selective inhibitor of CYP17A), which blocks androgen biosynthesis both within and outside the prostate cancer cells), and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for Orteronel (TAK- 700), ARN- 509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will present the rationale for the newly approved hormonal treatments, their indications and complications, and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about the potential upcoming hormonal treatments for mCRPC.
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    • "These natural or synthesized compounds can express certain influence on different mechanisms of cancercells growth and, in that way, inhibit their proliferation. Steroidal compounds belong to a fundamental class of natural signalling molecules with very high potential for treatment of many types of diseases, including prostate cancer, breast cancer, colorectal cancer , brain tumor, cardiovascular and autoimmune disorders (Chen et al., 2009; Recht et al., 2013; Knutson and Lange, 2014; Vaklavas et al., 2011; Yu et al., 2013; Richmond et al., 2014), etc. Because of very wide spectrum of compounds which have low, moderate or high cytotoxic activity toward certain cancer cells, it is very useful to establish criteria for their selection which will be used for further detailed in vitro and in vivo studies of their desired or side effects. "
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    ABSTRACT: The present paper deals with prediction of cytotoxic activity of 17-picolyl and 17-picolynilidene androstane derivatives towards aromatase negative prostate cancer cell lines (PC-3). The prediction was achieved applying artificial neural networks (ANNs) method on the basis of molecular descriptors. The most important descriptors (skin permeability (SP), Madin-Darby canine kidney cell permeability (MDCK) and universal salt solubility factor (S+SF)) were selected by using stepwise selection coupled with partial least squares method. The ANN modelling was carried out in order to obtain reliable models which can facilitate further synthesis of androstane derivatives with high antiproliferative activity towards PC-3 cell lines. The modelling procedure resulted in three ANN models with the best statistical performance. The obtained results show that the established ANN models can be applied for required purpose.
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