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: 24.73). 10/2009; 10(10):981-91. DOI: 10.1016/S1470-2045(09)70229-3
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Howard I Scher, Oct 08, 2014
  • Source
    [Show abstract] [Hide abstract]
    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.
    European Journal of Pharmaceutical Sciences 05/2014; DOI:10.1016/j.ejps.2014.05.031 · 3.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.
    05/2013; 2013:981684. DOI:10.1155/2013/981684
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent therapeutic advances for managing advanced prostate cancer include the successful targeting of the androgen-AR axis with several new drugs in castrate resistant prostate cancer including abiraterone acetate and enzalutamide (MDV3100). This translational progress from "bench to bed-side" has resulted in an enlarging repertoire of novel and traditional drug choices now available for use in advanced prostate cancer therapeutics, which has had a positive clinical impact in prolonging longevity and quality of life of advanced prostate cancer patients. In order to further the clinical utility of these drugs, development of predictive biomarkers guiding individual therapeutic choices remains an ongoing challenge. This paper will summarize the potential in developing predictive biomarkers based on the pathophysiology of the androgen-AR axis in tumor tissue from patients with advanced prostate cancer as well as inherited variation in the patient's genome. Specific examples of rational clinical trial designs incorporating potential predictive biomarkers from these pathways will illustrate several aspects of pharmacogenetic and pharmacogenomic predictive biomarker development in advanced prostate cancer therapeutics.
    Advances in Urology 08/2012; 2012:781459. DOI:10.1155/2012/781459