Urological Trainee’s Prize
The Urological Trainees’ Prize, presented in memory of the late Mr Patrick Doyle, is awarded annually at the East Anglian Urologists’ Regional meeting in December for a presentation on an audit-related topic.
The prize for December 2012 was awarded to Tom Mitchell, Antonio Ramos-Montoya, Marco Di Antonio,Pierre Murat, Stephan Ohnmacht, Sarah Jurmeister, Marialuisa Micco, Lee Fryer,Shankar Balasubramanian, Stephen Neidle, David E. Neal, Cambridge.
The winning abstract:
Androgen receptor (AR) signalling remains an important regulatory pathway in castrate resistant prostate cancer, and its transcriptional down-regulation could provide a new line of therapy. A number of small-molecule ligands have previously demonstrated the ability to stabilize G-quadruplex structures and affect gene transcription for those genes whose promoters contain a quadruplex-forming sequence. Herein, we report the formation of new G-quadruplex structure present in the AR promoter in a transcriptionally important location. NMR spectroscopy, circular dichroism, UV spectroscopy and UV thermal melting experiments have been performed to confirm that this sequence does form a G-quadruplex. Fluorescence resonance energy transfer (FRET) melting studies have identified a novel compound, MM45, which stabilizes this G-quadruplex at sub-micromolar concentrations. The effects of MM45 have been investigated in prostate cancer cell lines.
It has been shown to be more efficacious in inhibiting cell growth in AR expressing (including hormone insensitive) cell lines, in comparison to AR negative prostate cancer cell lines. A reporter assay intended to isolate the effect of MM45 on the G-quadruplex sequence, showed dose-dependent transcriptional repression only when the G-quadruplex sequence is present. Dose-dependent transcriptional repression of the AR by MM45 has been demonstrated both at a protein and mRNA level. This proof of concept study paves the route towards a potential alternative treatment pathway in castrate resistant prostate cancer.