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2024 The John Black Charitable Foundation – PCF Challenge Award

Developing Novel and Transformative Therapeutic Strategies Targeting mRNA translation for the Treatment of Molecularly Defined Prostate Cancer Subtypes

Principal Investigators: Adam Sharp, MD, PhD (The Institute of Cancer Research, London, UK), Johann de Bono, MD, PhD (The Institute of Cancer Research, London, UK), Andrew Hsieh, MD (Fred Hutchinson Cancer Center), Marco Bezzi, PhD (The Institute of Cancer Research, London, UK)

Young Investigators: Joe Taylor, PhD, (The Institute of Cancer Research, London, UK), Steven Blinka, MD, PhD (Fred Hutchinson Cancer Center)

Description:

  • New therapies including androgen receptor (AR) signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC). Despite these advances, treatment resistance is inevitable and mCRPC remains fatal. The development of new efficacious prostate cancer therapies with novel mechanisms of action remains an urgent unmet clinical need.
  • Dr. Adam Sharp and team have found that regulators of mRNA translation drive prostate cancer treatment resistance and may be therapeutic targets. 
  • In this project, the team will develop a suite of therapeutic strategies targeting mRNA translation to selectively kill specific molecular subtypes of lethal prostate cancer as a novel precision medicine approach.
  • The team will develop and validate a biomarker assay to identify prostate cancer molecular subtypes with dysregulation of the mRNA translation cellular process. 
  • Molecular responses to new and existing inhibitors of mRNA translation will be evaluated to identify prostate cancer molecular subtypes that respond robustly to these therapies. 
  • The team will also identify rational synergistic treatment combinations that will enhance the anti-tumor activity of therapies targeting mRNA translation.
  • If successful, this project will directly lead to clinical trials testing new mRNA translation-targeting therapies in a molecularly stratified prostate cancer patient population. 

What this means to patients: Metastatic castration-resistant prostate cancer (mCRPC) remains an uncurable disease, as nearly all patients will develop resistance to existing therapies. Dr. Sharp and team have identified altered mRNA translation as a key driver of treatment resistance and potential therapeutic target. This project will establish biomarkers for identifying patients with altered mRNA translation and determine the pre-clinical treatment efficacy of inhibitors of mRNA translation. This will lead to new clinical trials, and may result in new life extending precision medicine strategies for patients with currently lethal disease.