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 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 to Krüppel associated box (KRAB) or MAD-SID dominant transcription repression domain. These engineered repressors have been shown 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 LNCaP cells decreases active histone modification which leads to down-regulation of target gene expression. We have also demonstrated that the repressors are effective in models of castration resistance, for instance presence of mutants of the AR and increased co-activators expression. The ultimate goal is to create a novel 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.
Funding: Prostate Cancer UK.
Presenting Author: Flavia Marialucia Fioretti, Department of Surgery and Cancer, Imperial Centre of Translational and Experimental Medicine, Imperial College London, London W12 0NN, UK. Email: firstname.lastname@example.org