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2019 PCF VAlor Challenge Award

Targeting Castration Resistant Prostate Cancer with Novel Onco-Metabolic Inhibitors

Principal Investigators: Salma Kaochar, PhD (Baylor College of Medicine), Nicholas Mitsiades, MD, PhD (Baylor College of Medicine)

Co-Investigators: Michael Ittmann, MD, PhD (Baylor College of Medicine/Michael E. DeBakey Veterans Affairs Medical Center), Anita Sabichi, MD (Baylor College of Medicine/Michael E. DeBakey Veterans Affairs Medical Center), Cristian Coarfa, PhD (Baylor College of Medicine), Lori Banks, PhD (Baylor College of Medicine), Lutfi Abu Elheiga, PhD (Baylor College of Medicine)

Description:

  • Altered metabolism is a critical factor in prostate cancer progression, as cancer cells depend on increased energy and production of metabolites including lipids and cholesterol to maintain rapid cell growth. There are currently no approved drugs for prostate cancer that target altered metabolism.
  • The sterol regulatory element binding proteins (SREBPs) are master regulators of the enzymes that synthesize cholesterol and unsaturated fatty acids. SREBPs are frequently overexpressed in prostate cancer and are associated with disease aggressiveness and unfavorable outcomes. Inhibiting SREBPs may represent a promising new treatment strategy for metabolically driven tumors such as prostate cancer.
  • Salma Kaochar and team will investigate the therapeutic potential of targeting SREBPs in prostate cancer.
  • The team will investigate the expression of SREBPs in large prostate cancer patient cohorts, and determine their associations with clinical factors including cancer aggressiveness and patient outcomes.
  • Whether SREBP expression correlates with other prostate cancer oncogenic pathways such as the androgen receptor (AR), MYC, and EZH2, will be determined.
  • FGH-1927 is a novel SREBP-inhibitor with promising drug-like properties that was originally developed for the treatment of obesity and metabolic disorders and has not yet been tested in cancer. The team will determine the anti-cancer activity and mechanism of action of FGH-1927 in preclinical prostate cancer models.
  • If successful, this project will establish key proof-of-concept mechanistic, efficacy and safety data for the use of a novel small molecule inhibitor of SREBPs for the treatment of lethal castration resistant prostate cancer (CRPC).

What this means to patients: Increased production of lipids and cholesterol are a hallmark of lethal prostate cancer. Dr. Kaochar and team will investigate the potential for targeting SREBPs, master regulators of lipid and cholesterol synthesis, as a novel treatment strategy in prostate cancer. This may lead to a new class of treatments for prostate cancer that may have particular relevance in prostate cancer patients who are obese, are African American, or have castration resistant prostate cancer (CRPC), as these are even more highly associated with altered metabolism.