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2024 PCF Challenge Award

Donors: Anonymous, Bill Ackman and Neri Oxman, Adam Aron (AMC Cares), Greg Brown, William Corry, Jason Safriet, Jack Hidary, Asha Jadeja

Michael Freeman, PhD
James Turkson
Ramachandran Murali

Novel Inhibitors of Prostate Cancer Lineage Plasticity and Therapy Resistance

Principal Investigators: Michael Freeman, PhD (Cedars-Sinai Medical Center), James Turkson, PhD (Cedars-Sinai Medical Center Medicine), Ramachandran Murali, PhD (Cedars-Sinai Medical Center)

Co-Investigators: Michael Jung, PhD (University of California, Los Angeles), Sungyong You, PhD (Cedars-Sinai Medical Center), Francisco Javier Lopez-Tapia, PhD (Cedars-Sinai Medical Center)

Young Investigator: Qian Galaxy Yang, PhD

Description:

  • Androgen receptor (AR)-targeted therapy is the standard of care for advanced or aggressive prostate cancer, but treatment resistance commonly occurs, and patients develop castration-resistant prostate cancer (CRPC), for which no curative treatments have yet been developed. New therapies that target treatment resistance mechanisms are urgently needed for patients with CRPC.
  • ONECUT2 is a master regulator of an extensive lineage plasticity signaling network in prostate cancer, that may drive several mechanisms of treatment resistance and CRPC progression.
  • Dr. Michael Freeman and his team have confirmed that ONECUT2 is a promising therapeutic target in prostate cancer and have developed novel ONECUT2 inhibitors that have promising pharmacology and preclinical anti-tumor activity. 
  • In this project, the team will further optimize ONECUT2 inhibitors using iterative structural, chemical and biological approaches. 
  • The structure of the ONECUT2 inhibitor/ ONECUT2 complex and the specific molecular interactions will be defined. 
  • Next-generation ONECUT2 inhibitors with improved potency, selectivity, safety and pharmacokinetic properties will be developed.
  • The effect of next-generation ONECUT2 inhibitors on ONECUT2 function will be determined. 
  • If successful, this team will develop a novel treatment to disrupt the emergence of treatment-resistant cancer and progression of CRPC, that can be advanced to clinical trials.

What this means to patients: There are currently no curative treatments for patients with metastatic prostate cancer or aggressive disease that developed resistance to AR-targeted therapies. Dr. Freeman’s team will develop a novel ONECUT2 inhibitor for the treatment of CRPC, and will define the molecular and biological mechanisms of action of this treatment in preparation for advancement to clinical trials.