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Targeting the PTGES3-AR axis in Advanced Prostate Cancer

Principal Investigators:
Luke Gilbert, PhD (University of California, San Francisco)
Felix Feng, MD (University of California, San Francisco)
Kevan Shokat, PhD (University of California, San Francisco)
Michelle Arkin, PhD (University of California, San Francisco)

Co-Investigators: Haolong Li, PhD (University of California, San Francisco)

Description: 

  • The androgen receptor (AR) is the primary driver of prostate cancer and hence the primary therapeutic target. Unfortunately, resistance to AR-targeted therapy is common, and disease progresses to castration-resistant prostate cancer (CRPC), for which no curative therapy currently exists.
  • AR-targeted therapy resistance is often driven by tumor cells alterations that reactivate AR activity. New treatment strategies to prevent AR activity remain urgently needed.
  • Luke Gilbert and team have developed a novel approach to identifying new genes that regulate AR activity.
  • One of the genes identified is prostaglandin E synthetase (PTGES3), which was found to be required for AR activity and growth of AR-driven prostate cancer cells.
  • PTGES3 thus may be a new therapeutic target for prostate cancer.
  • In this project, the team will identify the mechanisms by which PTGES3 regulates AR.
  • The team will determine whether PTGES3 is a biomarker of resistance to AR-targeted therapy using samples from several randomized clinical trials.
  • Finally, the team will develop PTGES3-inhibitors that have efficacy in prostate cancer.
  • If successful, this team will develop a new treatment approach that can prevent and/or overcome CRPC.

What this means to patients: AR-targeted therapy is the primary treatment for prostate cancer, however treatment resistance is nearly inevitable and patients progress to lethal disease. Dr. Gilbert and team have identified PTGES3 as a critical regulator of AR that drives CRPC. The team will investigate the biology by which PTGES3 drives prostate cancer progression and treatment resistance, and develop new treatments that target PTGES3, which may extend and improve the lives of patients.