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2023 John Black Charitable Foundation – PCF Young Investigator Award

N-Acetyl Aspartate Sustains Castration Resistant Prostate Cancer through Glucocorticoid Induced Sphingolipid Metabolism

Mark Salji, PhD, MB, Bchir
University of Glasgow – Cancer Research UK Beatson Institute

Mentors: Hing Leung, Nima Sharifi, Ruth Morgan

Description:

  • Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer that has developed resistance to standard hormonal therapy. Understanding the mechanisms that drive the development of CRPC are critical to developing new and more effective treatments.
  • The glucocorticoid receptor (GR) is related to the androgen receptor (AR) with some overlap in metabolism pathways and function, and may act as a bypass mechanism for tumors to overcome AR-inhibition in some patients with CRPC. Aberrant activation of GR may also account for the aggressive nature of CRPC in patients with advanced prostate cancer and obesity. However, targeting the GR pathway directly has resulted in side effects that have limited drug development; novel approaches to target GR are needed.
  • Mark Salji and team are investigating the role of metabolites that may be downstream of GR in CRPC. They hypothesize that N-acetyl aspartate (NAA), a metabolite product of the prostate cancer enzyme PSMA, may be driven by GR activation and drive CRPC.
  • In this project, Dr. Salji and team will identify the major source of NAA in CRPC and determine whether NAA supports sphingolipid metabolism. Whether this is a mediator of GR pathway activation, driving CRPC, will be investigated in preclinical models.
  • Whether the NAA pathway can be inhibited by targeting PSMA and sphingolipids will be determined in preclinical models of CRPC, to provide the rationale for future clinical trials.
  • If successful, this project will characterize the role of NAA in CRPC and identify therapeutic approaches to target the NAA pathway as a potential downstream mediator of GR in CRPC. This may lead to new treatment approaches for patients with GR-driven CRPC.

What this means to patients: The glucocorticoid receptor (GR) appears to drive the development of treatment resistance in some patients with CRPC, and may play a role in the links observed between obesity and more aggressive disease. Dr. Salji and team will determine the role of NAA as a potential downstream mediator of GR activation in CRPC, and identify approaches for targeting the NAA pathway. This could lead to new treatments for CRPC as well as be of interest to cardiovascular and metabolic research areas and the wider cancer metabolism research community.