Abstract 1728: Membrane androgen receptor ligands: a novel therapeutic approach for the treatment of cancer

Abstract Membrane Androgen Receptor (mAR) is a novel, yet of unknown identity, membrane receptor frequently over-expressed in aggressive prostate cancer. mAR is not related to the classical intracellular androgen receptor (AR), a well known therapeutic target for prostate cancer treatment. Consequently, mAR induces tumour cell death by apoptosis in both AR-positive and AR-negative cell lines or in the presence of anti-androgens (e.g. flutamide). Early experimental results with membrane-targeted steroids (androgen-albumin conjugates) have proved the validity of mAR as a novel target of cancer therapy, as based on the anti-cancer action observed in prostate xenograft models (reviewed in IUBMB Life. 2009 Jan;61(1):56-61). In this study, we describe novel small molecule steroidal mAR ligands that exhibit in vitro anti-cancer activity in the nanomolar range in prostate cancer cell lines. Furthermore, and as based on the identification of functional membrane androgen receptors in non-prostate cancer cells by immuno-fluorescence analysis, we show that selective novel mAR ligands exert broad anti-cancer action in additional cell line panels including colon, non-small cell lung cancer, central nervous system, breast or multi drug resistant cells. Notably, our compounds are selective for mAR binding since control displacement assays failed to identify significant interactions with recombinant Androgen Receptors. To assess the anti-cancer of our compounds in vivo, we measured the ability of a prototype mAR ligand, MDX-146, to inhibit tumour growth of human PC-3 prostate cancer xenografts. Our results show clear tumour growth inhibition effects of MDX-146 in animals and propose a potential therapeutic role of specific mAR ligands for the treatment of prostate and other cancers. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1728.