2025 Helmy Eltoukhy – PCF Young Investigator Award

Metabolic Synthetic Lethality in SPOP-Mutant Prostate Cancer

Joanina Gicobi, PhD
Mayo Clinic

Mentors: Jacob Orme, Elisabeth Heath

Description:

• Mutations in the SPOP gene drive development of ~10% of prostate cancer cases and represent a distinct subtype. Although initially sensitive to androgen deprivation therapy, most SPOP-mutant prostate cancers progress into lethal castration-resistant prostate cancer (CRPC). There is a critical need to develop novel therapeutic approaches for these patients. 
• Dr. Gicobi and team have found that SPOP-mutant prostate cancers have distinct metabolic alterations, and hypothesize that these may lead to unique vulnerabilities and dependencies that can be therapeutically targeted. 
• This project will define the mechanisms of altered metabolism in SPOP-mutant prostate cancer cells, and determine whether the metabolic enzymes that SPOP-mutant prostate cancer cells rely on may represent unique therapeutic targets.
• SPOP activity also impacts anti-cancer immune responses. This project will also investigate whether the distinctive oncometabolites produced in SPOP-mutant prostate cancer dampen responses to cancer immunotherapy, and explore therapeutic strategies to reverse these effects.
• If successful, this project will provide invaluable mechanistic insights into the role of SPOP in the metabolism of prostate cancer and identify novel druggable targets for patients with SPOP-mutated CRPC.

What this means to patients: Approximately 10% of patients with prostate cancer have SPOP-mutations in their tumors, which represent a unique biology that deserves research into unique treatment strategies. This project will define the distinctive alterations in metabolism and immune functions in SPOP-mutant prostate cancer and identify vulnerabilities that can be therapeutically targeted. This could lead to new treatments for these patients, who would otherwise ultimately develop lethal prostate cancer.