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2024 PCF Young Investigator Award

Development of Inhibitor Targeting Master Regulator ONECUT2 for Advanced Prostate Cancer

Brad Gallent, MD, PhD
Cedars-Sinai Medical Center

Mentors: Michael Freeman, PhD; Ramachandran Murali, PhD

Description:

  • ONECUT2 is a master transcription factor upregulated in prostate cancer that drives phenotypic plasticity and treatment resistance. ONECUT2 has also been implicated in driving multiple other cancer types such as breast, lung, cervical, liver, stomach, and colon cancer. These features suggest ONECUT2 may be a promising therapeutic target, and warrant studies to develop ONECUT2-inhibitors for cancer therapy.
  • Dr. Brad Gallent’s project aims to develop ONECUT2 inhibitors for prostate cancer and characterize their mechanism of action. 
  • Small molecule ONECUT2 inhibitors which suppress prostate cancer metastases in mouse models and synergize with standard-of-care hormone treatment have been identified. 
  • ONECUT2 inhibitor chemical groups important for binding and inhibiting ONECUT2 activity will be identified.
  • Atomic-resolution structural techniques will be applied to visualize the ONECUT2 binding site and mechanism of action of these inhibitors. 
  • If successful, this project will result in atomic-level knowledge of how to optimize activity of ONECUT2 inhibitors, and further the development of a novel ONECUT2-targeting therapeutic for patients with prostate cancer.

What this means to patients: ONECUT2 is a promising therapeutic target for prostate cancer, and the development of effective ONECUT2 inhibitors is highly warranted. Dr. Gallent’s project will establish the chemical and atomic-level features of optimal ONECUT2 inhibitors, paving the way for trials testing novel ONECUT2 inhibitors in combination with standard hormone therapy for patients with metastatic prostate cancer. These studies will also illuminate how cutting-edge structural biology technologies can be applied to understand and target oncogenic transcription factors for prostate cancer treatment.