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2023 John Black Charitable Foundation-PCF Challenge Award

Metabolic Imaging and Targeted Radionuclide Combination Treatment of Prostate Cancer Bone Metastases

Principal Investigators: Edward O’Neill, PhD (University of Oxford), Claire Edwards, PhD (University of Oxford)

Co-Investigator: Ian Mills, PhD (University of Oxford)

Collaborators: Massimo Loda, MD (Weill Cornell Medicine), Josephine Bunch, PhD (National Physical Laboratory), Mark Konijnenberg, PhD (Erasmus MC), Gail Risbridger, PhD (Monash University), Renea Taylor, PhD (Monash University), Peter Croucher, PhD (Garvan Institute of Medical Research), James McCullagh, PhD (University of Oxford), Daniel McGowan, PhD (Oxford University Hospitals NHS Trust), Neel Patel, MD, PhD (Oxford University Hospitals NHS Trust), Price Jackson, PhD (Peter MacCallum Cancer Centre)

Description:

  • The PSMA-targeted radionuclide therapy LuPSMA has recently been approved for the treatment of patients with mCRPC whose tumors are positive on PSMA PET imaging. LuPSMA consists of a radioactive isotope attached to a small molecule targeting PSMA, a protein expressed on most prostate cancer cells.
  • Despite the promising activity of LuPSMA, all patients eventually progress. Understanding the mechanisms of resistance to LuPSMA is critical for improving the efficacy of this treatment.
  • PSMA is an enzyme that regulates folate metabolism. Dr. Edward O’Neill and team hypothesize that PSMA’s folate metabolism activity, which can be used to create antioxidants, may contribute to resistance to LuPSMA.
  • In this project, the team will investigate whether FDG PET imaging, which visualizes tumors with high metabolic activity, can predict radiation sensitivity of tumors and responsiveness to LuPSMA.
  • Whether increased PSMA levels can contribute to resistance to LuPSMA through increasing anti-oxidant metabolism will be determined.
  • The team will investigate whether treatments that inhibit folate or anti-oxidant metabolism increase the efficacy of LuPSMA. The role of FDG PET + PSMA PET for predicting and monitoring responses to this treatment combination will be investigated.
  • Finally, the impact of these metabolic pathways on prostate cancer cell dormancy will be investigated. Whether metabolic inhibitors combined with LuPSMA can prevent reactivation of dormant prostate cancer cells will be determined.
  • If successful, this project will define the role of tumor metabolism in resistance to LuPSMA, determine an optimal way to use PSMA PET and FDG PET to select patients for treatment with LuPSMA, and identify metabolically directed combination therapies to overcome metabolic radiation-resistance.

What this means to patients: Understanding resistance to LuPSMA is critical for improving treatment of patients with advanced prostate cancer. This team will determine the role of tumor metabolism in treatment responses to LuPSMA, and the potential for these tumor metabolic pathways as biomarkers and therapeutic targets in prostate cancer.