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2024 Republic National Distributing Company (RNDC) – PCF Challenge Award

Targeting CRPC at the Intersection of Alternative Polyadenylation and Cellular Plasticity

Principal Investigators: Scott Dehm, PhD (University of Minnesota), Justin Drake, PhD (University of Minnesota), Hongbo Pang, PhD (University of Minnesota)

Co-Investigators: Emmanuel Antonarakis, MD (University of Minnesota), Justin Hwang, PhD (University of Minnesota)

Young Investigator: Kiel Tietz, PhD (University of Minnesota)

Description:

  • Castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer characterized by its resistance to standard androgen receptor (AR) targeting therapies. While most CRPC tumors continue to depend on the AR pathway for growth, resistance mechanisms often evolve, necessitating the exploration of new therapeutic targets.
  • Dr. Scott Dehm and team have identified two key ways CRPC tumors develop resistance: 1) Genetic plasticity whereby some tumors amplify the AR gene on small, free-floating pieces of DNA (extrachromosomal DNA, or ecDNA) to sustain the AR pathway despite therapy, or 2) Cell type plasticity whereby some tumors transition to alternative cell types (basal, club, and hillock cells) that do not depend on the AR pathway, rendering AR-targeting drugs ineffective.
  • The team has uncovered mRNA polyadenylation as a crucial RNA regulatory process that is altered in CRPC tumors to allow continued growth and progression.
  • In this project, the team will define the landscape of mRNA polyadenylation in prostate cancers with AR ecDNA and in those that have undergone cellular transitions.  Their goal is to understand the role of altered mRNA polyadenylation in CRPC genetic and cellular plasticity, and identify distinct mRNA polyadenylation targets that can be leveraged for developing novel prostate cancer therapeutics.
  • To translate these findings into potential treatments, the team will evaluate whether blocking key mRNA polyadenylation targets can effectively disrupt CRPC tumors displaying genetic or cellular plasticity.
  • If successful, this project will define the roles of altered mRNA polyadenylation in CRPC and develop innovative treatments targeting RNA regulatory processes that drive CRPC growth and progression.

What this means to patients: Castration-resistant prostate cancer (CRPC) remains an incurable form of advanced prostate cancer for which new treatment strategies are urgently needed. Dr. Dehm and team have identified altered mRNA polyadenylation and cellular plasticity as drivers of CRPC. They will define the role of mRNA polyadenylation in prostate cancer and develop new treatments to target the cancer-driving genes required for CRPC cellular plasticity. By addressing the critical challenge of therapy resistance in CRPC, this work holds the potential to significantly advance the treatment landscape for patients afflicted with this deadly disease.