The novel anti-androgen candidate galeterone targets deubiquitinating enzymes, USP12 and USP46, to control prostate cancer growth and survival

Abstract

// Urszula L. McClurg 1, 4, * , Mahsa Azizyan 1, * , Daniel T. Dransfield 2, 5 , Nivedita Namdev 2 , Nay C.T.H. Chit 1 , Sirintra Nakjang 3 and Craig N. Robson 1, * 1 Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK 2 Tokai Pharmaceuticals, 255 State Street, Boston, MA 02109, USA 3 Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK 4 Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK 5 Current address: Siamab Therapeutics, Suite 100, Newton, MA 02458, USA * These authors contributed equally to these work Correspondence to: Craig N. Robson, email: Craig.Robson@ncl.ac.uk Keywords: prostate cancer; castrate-resistance; USP12; USP46; galeterone Received: February 01, 2018      Accepted: February 10, 2018      Published: May 18, 2018 ABSTRACT Metastatic castration resistant prostate cancer is one of the main causes of male cancer associated deaths worldwide. Development of resistance is inevitable in patients treated with anti-androgen therapies. This highlights a need for novel therapeutic strategies that would be aimed upstream of the androgen receptor (AR). Here we report that the novel small molecule anti-androgen, galeterone targets USP12 and USP46, two highly homologous deubiquitinating enzymes that control the AR-AKT-MDM2-P53 signalling pathway. Consequently, galeterone is effective in multiple models of prostate cancer including both castrate resistant and AR-negative prostate cancer. However, we have observed that USP12 and USP46 selectively regulate full length AR protein but not the AR variants. This is the first report of deubiquitinating enzyme targeting as a strategy in prostate cancer treatment which we show to be effective in multiple, currently incurable models of this disease.