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2024 The John Black Charitable Foundation – PCF Young Investigator Award

Investigating the Potential of Repurposing Anti-Diabetic/Obesity Drugs for the Treatment of Obesity-Driven Aggressive Prostate Cancer

Nil Grunberg, PhD
Imperial College London

Mentors: Claire Fletcher, PhD; Antonina Mitrofanova, PhD

Description:

  • Obesity is a global epidemic that will soon overtake smoking as the largest preventable risk factor for cancer. Every five-point increase in body-mass index increases risk of fatal prostate cancer (PC) by almost 10% and shortens the time to develop castration-resistance. However, mechanisms underpinning obesity-driven prostate cancer remain poorly understood. 
  • The prostate is surrounded by peri-prostatic adipose tissue (PPAT), and greater amounts of PPAT are associated with increased risk of lethal prostate cancer and reduced therapy-response. PPAT secretes hormones, adipokines/cytokines, and extracellular vesicles (EVs), which are tiny particles that transfer cargo including protein, lipids, metabolites and RNA from the parent cell to distant sites. These PPAT-secreted factors can promote the progression of other cancer types and deserve study in prostate cancer. 
  • Dr. Nil Grunberg is investigating how PPAT-secreted factors drive prostate cancer tumorigenesis, and whether FDA-approved anti-diabetic/obesity drugs (ADODs) such as Semaglutide, Tirzepatide and Metformin, can impact these factors and prevent prostate cancer progression.
  • The mechanisms behind ADOD reprogramming of PPAT adipocytes and the impact they have on prostate cancer cells will be investigated in matched patient PPAT/tumor tissues and genetically-engineered mouse models.
  • The effects of ADODs on prostate cancer cell behavior and agressiveness and whether treatment with ADODs can inhibit obesity-associated prostate cancer progression will be determined in models.
  • If successful, this project will illuminate the mechanisms by which peri-prostatic adipose tissue drives prostate cancer progression, and whether diabetic/obesity drugs can be repurposed as a cancer therapeutic, particularly in obese patients.

What this means to patients:
Obesity is a strong risk factor for prostate cancer development, progression, and mortality. Peri-prostatic adipose tissue (PPAT) is also associated with increased risk of lethal prostate cancer and reduced therapy-response. Dr. Grunberg’s project will improve knowledge of how obesity and PPAT drive prostate cancer, and determine the potential of Semaglutide/Tirzepatide as anti-cancer medications that could be combined with standard prostate cancer treatment in obese patients to reduce risk of increased mortality, cut treatment costs, and improve quality of life.