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2023 Leerom & Karolina Segal – PCF Young Investigator Award

Epigenetic and Metabolomic Vulnerabilities in ASCL1-Driven NEPC Subtype

Shaghayegh Nouruzi, PhD
University of British Columbia (UBC)

Description:

  • Androgen receptor signaling inhibitors (ARSIs) are newer, more potent treatments for advanced prostate cancer. Unfortunately, prostate cancers commonly develop treatment resistance to ARSIs, often through the emergence of AR-independent phenotypes, including neuroendocrine prostate cancer (NEPC). Alarmingly, no targeted therapies exist for NEPC, which stems from our poor understanding of the mechanisms underlying this lethal disease.
  • Shaghayegh Nouruzi and team have recently found that the transition of castration-resistant prostate cancer (CRPC) to NEPC is accompanied by an extensive epigenetic and transcriptional rewiring, governed by ASCL1. Further, ASCL1-high NEPC tumors have a distinct metabolic profile.
  • In this project, Dr. Nouruzi and team will evaluate the interplay between ASCL1, metabolism and epigenetic alterations, in the transition of CRPC to NEPC.
  • The epigenetic and metabolic landscape of CRPC, ASCL1-high NEPC, and ASCL1-low NEPC will be characterized, to determine the contribution of ASCL1 and metabolic rewiring in NEPC and identify epigenetic/metabolomic-based treatment vulnerabilities.
  • The mechanism by which ASCL1 alters metabolism to alter the epigenetic landscape in favor of the NEPC lineage will be determined.
  • The efficacy and biological effects of treating ASCL1-high NEPC with metabolic inhibitors will be investigated.
  • If successful, this project will define the role of ASCL1 and metabolic alterations in driving progression to NEPC and identify promising new metabolism-based treatment strategies for NEPC.

What this means to patients: NEPC is a highly aggressive form of CRPC, for which no effective treatments are currently available. Dr. Nouruzi and team will define the role of a novel driver of NEPC, ASCL1, and determine whether metabolic alterations underlie transition of CRPC to NEPC. This project will also define whether NEPC is sensitive to certain metabolic inhibitors, which could accelerate new treatment paradigms for patients with this otherwise lethal form of prostate cancer.