Principal Investigators: Nigel Mongan, PhD (University of Nottingham)

Co-Investigators: Victoria James, PhD (University of Nottingham), Catrin Rutland, PhD (University of Nottingham), Emad Rakha, MD (University of Nottingham), Jennie Jeyapalan, PhD (University of Nottingham), Rupert Fray, PhD (University of Nottingham), Nathan Archer, PhD (University of Nottingham), Brian Robinson, MD (Weill Cornell Medicine), Francesca Khani, MD (Weill Cornell Medicine), Simone de Brot, PhD, DVM (University of Bern), Jenny Persson, PhD (Umeå University & Malmö University, Sweden)

Description: 

• Androgen-targeted therapies such as enzalutamide are important treatments for advanced prostate cancer. Unfortunately, emergence of treatment resistance and progression to castration resistant prostate cancer (CRPC), appears inevitable. There is an urgent need for new approaches to prevent or reverse the development of CRPC.
• Tumors that develop resistance to androgen-targeted therapies often exhibit increased expression of full-length androgen receptor (AR) and shorter pathogenic variants, including ARv7, which lack the AR protein domain targeted by these treatments. AR-variants are thought to be key mediators of androgen-targeted therapy resistance. However, how their expression levels are regulated in CRPC remains unclear.
• Dr. Nigel Mongan and team are studying how androgen-targeted therapies induce expression of AR-variants. The team has previously found that RNA methylation plays a major role in regulating what form of a gene is expressed as a protein and its levels.
• In this project, the team will investigate whether androgen-targeted therapies alter RNA methylation, including that of AR RNAs.
• The team has identified several enzymes involved in RNA methylation that may be involved and will determine whether their levels correlate with prostate cancer progression and treatment resistance in patient samples.
• The biology of how these RNA modifying enzymes impact prostate cancer biology and treatment resistance will be investigated in mouse prostate cancer models.
• Whether RNA methylation may be promising as a therapeutic target will be determined.
• If successful, this project will determine if and how RNA methylation impacts prostate cancer biology and whether RNA methylation enzymes have potential as therapeutic targets.

What this means to patients:  Dr. Mongan and team are studying the novel field of RNA methylation in prostate cancer.  They will determine if and how RNA methylation alterations impact disease progression and treatment resistance.  Finally, they will determine the potential of targeting RNA methylation as a novel treatment for preventing or reversing CRPC, which may lead to re-appropriation of such treatments that are already being developed for leukemia.