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2021 Art Kern in Honor of Plum and Jonathan W. Simons, MD-PCF Young Investigator Award

Investigating PTGES3 as a Novel Therapeutic Target in Advanced Prostate Cancer

Haolong Li, PhD
University of California, San Francisco

Mentors: Felix Feng, MD, Luke Gilbert, PhD, Kevan Shokat, PhD

Description:

  • The androgen receptor (AR) is the central therapeutic target for advanced prostate cancer. While treatments that directly target AR prolong patient survival, aggressive prostate cancers invariably find a way to evade these therapies, most commonly by restoring AR activity via a variety of clinically validated mechanisms. Comprehensively understanding the protein regulation machinery of AR and identifying alternative therapeutic targets are crucial for effective treatment of this disease.
  • Dr. Haolong Li and colleagues have developed a technology to identify regulators of AR that may be promising therapeutic targets. The top novel targetable hit identified was prostaglandin E synthetase (PTGES3). PTGES3 was further validated as essential for cell growth and survival in all AR-driven prostate cancer models tested.
  • In this project, Dr. Li is validating PTGES3 as a new biomarker and therapeutic target in prostate cancer.
  • The mechanisms by which PTGES3 regulates AR will be determined, including how PTGES3 regulates AR protein levels and AR-mediated gene expression.
  • Data from three ongoing clinical trials will be used to prospectively validate PTGES3 overexpression as a biomarker of resistance to AR-directed therapies.
  • Novel lead compounds for PTGES3 inhibition have been developed, and their efficacy will be tested in preclinical prostate cancer models.
  • If successful, this project will inform on the biology of PTGES3 in prostate cancer and validate it as a promising new biomarker and treatment target. The preclinical drug developed from this work may eventually benefit patients with aggressive prostate cancer that is resistant to current AR-directed therapies.

What this means to patients: PTGES3 is a promising new treatment target recently identified by Dr. Li and colleagues. This study will shed light on the biology underlying this novel AR regulator from a mechanistic, biomarker, and therapeutic approach. This will enhance our fundamental understanding of AR biology, and contribute to new therapeutic approaches towards AR in advanced prostate cancer.