by Charlotte Bevan
Dr Claire Fletcher, of the Androgen Signalling Laboratory, Division of Cancer, has been awarded a prestigious Young Investigator Award by the Prostate Cancer Foundation of the USA. The stated aim of the PCF in creating these awards, which are very rarely awarded outside of the US, is “to identify a cohort of future research leaders who will keep the field of prostate cancer research vibrant with new ideas.”
Claire will be using the award to pursue her innovative translational research programme at Imperial College, mentored both by Professor Charlotte Bevan in her host laboratory and also by Prof Johann de Bono at the Institute of Cancer Research, cementing and developing the collaboration between the 2 laboratories and indeed institutes. Her work focuses on identification of microRNA drivers of therapy resistance in prostate cancer, with the aim of both increasing therapy options and also of providing biomarkers to enable effective patient stratification.
“I am thrilled to have received a Prostate Cancer Foundation Young Investigator Award. This grant will allow me to vastly accelerate our promising research into the mechanisms through which prostate cancers continually evolve to develop resistance to even the most effective drugs – an area which remains poorly understood.
In the future, this knowledge will help us to develop more effective therapeutics and tailor treatments to individual patients.” – Dr Claire Fletcher.
Systematic Identification of MicroRNA Drivers of Resistance to Novel Therapeutics in Advanced Prostate Cancer – Exploitation as Stratification Biomarkers and Drug Targets
Prostate cancer (PC) is the most prevalent malignancy of Western males, affecting 1 in 8 men in their lifetime. Relapse on first-line anti-androgen treatment occurs almost invariably, leading to advanced ‘castration-resistant PC (CRPC), metastasis and patient death. Next-generation therapeutics that target the androgen receptor (AR) or alternative oncogenic signalling pathways, alongside taxane-based chemotherapeutics, demonstrate efficacy in the CRPC setting. However, only 50% of men respond to taxane-based chemotherapy, and acquired resistance to novel AR-targetting agents is emerging due to intra-tumoral androgen production or AR amplification. This necessitates urgent identification of new therapeutics and drug targets for CRPC, and discovery of resistance-predicting biomarkers.
MiRs are small 18-22nt RNAs that negatively regulate gene expression. They can function as ‘oncomiRs’ or tumour suppressors and show altered expression in CRPC. They are readily detectable in bodily fluids from patients, demonstrating considerable biomarker potential, and represent ideal therapeutics due to their small size, high stability and low toxicity. I have previously demonstrated that miRs dramatically alter AR activity, growth and metastatic potential in CRPC and that levels of putative oncomiRs are altered by novel CRPC drug treatment. Further, miRs are associated with chemotherapy resistance.
This project will use small RNA sequencing and functional assays to identify miRs that play fundamental roles in development of resistance to mechanistically-distinct novel CRPC agents in clinically-relevant CRPC models, and will generate miR biomarker ‘signature’ arrays that can predict resistance to such therapeutics. This will inform clinical management of PC and avoid the considerable morbidity and toxicity of agents that may not benefit a given patient. Development of therapies targeting resistance-promoting miRs may provide an additional treatment option for CRPC patients, increasing disease survival.
Professor of Cancer Biology
Androgen Signalling Laboratory