Development of a transcriptional repressor based approach for the treatment of prostate cancer
File(s)
Author(s)
Fioretti, Flavia Marialucia
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2017-09
Date Awarded
2018-03
Advisor
Bevan, Charlotte
Ali, Simak
Sponsor
Prostate Cancer UK
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)