Understanding Aggression in Hereditary Prostate Cancer

Closing date: 15/03/2027

MB-PhD Studentship: Understanding Aggression in Hereditary Prostate Cancer

Lead Supervisors: Professor Robert Bristow
Lead Supervisors: Professor David Wedge, Professor Stephen Taylor, Dr Ashwin Sachdeva

Applications Deadline: Monday 15th March 2027
Interviews: Week commencing 3rd May 2027
Start date: September 2027

Project Keywords: BRCA2, MSH2, metabolism, genetic instability
Research Opportunity: MB-PhD Studentship

Project Outline

Preventing failure after initial local (surgery or radiotherapy) and hormone treatment provides the best opportunity to block the evolution of high-risk prostate cancer (PCa). We and others have published that the outcomes are very poor for 10% of localised prostate cancer patients who have germline defects in DNA Damage and Repair (DDRd) genes. These tumours show rapid development of metastatic castrate-resistant prostate cancer (mCRPC) due to resistance to androgen receptor inhibitors and present with increased stage, Gleason group pathologic grade (GG) 4-5 and de novo metastases.

The studentship is focused on understanding the genetic evolution and aggression of gBRCA2 and gMSH2 (MMR-mismatch repair) localised PCa, so as to better triage patients to optimized, targeted treatment for cure. A new multidisciplinary translational DDR clinic is now established at the Manchester Christie NHS Trust in which high-risk PCa patients with suspected germline DDR gene  mutations are consented by the MCRC Biobank for translational studies. Using immortalised treatment-naïve, primary prostate epithelial cells (PrECs) derived from radical prostatectomies of BRCA2 and MSH2 carrier patients, we have created the world’s first loss of function (LOF) BRCA2 models with CRISPR technology. We are also developing isogenic and syngeneic murine DVL3 (Tp53-/- /Pten-/-) models with DDR defects. 

Using these cell models, we will test the hypothesis that  mtBRCA2 and mtMSH2 prostate cancers have increased genetic instability due to acquired secondary somatic driver mutations; this may be augmented by tumour hypoxia.  We will assess DNA repair and clonal evolution in DDRd cells that are defective in cancer driver genes (TP53 or RB) or are hypoxic, similar to that found in sub-regions of tumours. Understanding the mechanistic basis of aggression allows us to design clinical trials that target these tumours with novel therapies such as PARP1 or cdk4/6 inhibition or anti-hypoxia therapies. This gives hope to men with DDRd prostate cancer and provide better outcomes in an otherwise lethal disease. 

Applications for this project are now open. Please complete your application on The University of Manchester Postgraduate Application Portal.

About Prof. Robert Bristow (project Lead Supervisor)

Professor Robert Bristow MD PhD FRCPC is University Professor of Cancer Studies in the Division of Cancer Sciences (The University of Manchester) and Chief Academic Officer at The Christie NHS Foundation Trust. Professor Robert Bristow joined the University of Manchester as Director of the Manchester Cancer Research Centre (MCRC) in August 2017 with a remit to developing a new cancer strategy for Manchester with a cancer team science approach. The MCRC is a unique partnership between Cancer Research UK, The University of Manchester and the Christie NHS Foundation Trust.

His primary research interests are in tumour hypoxia, DNA damage signalling and DNA repair in tumours, and the genomics of prostate cancer progression and cancer treatment response. He is particularly interested in novel clinical trials that intensify cancer therapy to prostate cancer patients whose tumours harbour aggressive genetic changes and hypoxic sub-regions.

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