Development of a transcriptional repressor based approach for the treatment of prostate cancer

Abstract

Prostate cancer is currently treated with hormonal therapies, which aim to block the production and/or action of androgens. However, tumours eventually progress to castration-resistant prostate cancer and there is therefore still a great need for new therapeutic approaches. We have designed and tested engineered repressors which could be effective in circumstances where current therapies fail. These consist of two modules: an interaction domain, which binds directly to the androgen receptor (AR), and a transcriptional co-repressor domain, that promotes the formation of a transcriptional inhibitory complex. The most effective interaction domain tested is part of the AR N-terminus itself (aa 1-54), containing the 23FQNLF27 motif, which has been fused, respectively, to the Krüppel associated box (KRAB) and the MAD-SID dominant transcription repression domain. I have shown these engineered repressors to suppress AR activity through disruption of the AR N-/C-terminal interaction, destabilization of the AR protein and promoting the recruitment of histone deacetylase (HDACs) to AR. Expression of engineered repressors in prostate cancer cells leads to down-regulation of target gene expression. I have also demonstrated that the repressors are effective in models of castration resistance, for instance presence of mutant forms of the AR and increased co-activator expression. The ultimate goal is to create a novel highly specific therapeutic effective in resistant stages of the disease, that can be administered systemically or delivered specifically to the prostate, therefore minimizing the deleterious side-effects associated with current therapies used to target the androgenic axis.