AACR 2017: PRMT1 Identified as Potential Druggable Target for Pancreatic Cancer

Key Points

  • Through PILOT, researchers discovered novel epigenetic drivers in pancreatic ductal adenocarcinoma, including PRMT1 in tumors that harbor KRAS mutations on the background of p53.
  • The team confirmed that genetic “knockdown” of PRMT1 significantly impaired pancreatic ductal adenocarcinoma cell growth in vitro through use of genetic editing tools, including CRISPR and small hairpin RNA.

A protein known as arginine methyltransferase 1 (PRMT1) may be a potential therapeutic target for pancreatic ductal adenocarcinoma, according to results presented by Giuliani et al the 2017 Annual Meeting of the American Association for Cancer Research (AACR) in Washington, DC (Abstract 3016).

PRMT1 is involved in a number of genetic processes, including gene transcription, DNA repair, and signaling.

“Our study has identified and validated for the first time an arginine methyltransferase as a novel genetic vulnerability in [pancreatic ductal adenocarcinoma],” said Giulio Draetta, MD, PhD, Professor of Genomic Medicine and Director of Institute for Applied Cancer Science (IACS) at The University of Texas MD Anderson Cancer Center. “These findings strongly suggest a role for PRMT1 in [pancreatic ductal adenocarcinoma] development, and illuminate a path toward the development of therapies for patients in desperate need of innovative solutions.”

Study Findings

Various treatment regimens have failed to improve pancreatic ductal adenocarcinoma patient survival, driving the critical need for finding druggable targets essential for tumor maintenance. Dr. Draetta’s team developed an in vivo platform called Patient-Based In Vivo Lethality to Optimize Treatment (PILOT), a technology enabling systemic identification of tumor vulnerabilities in patient-derived tumors. Through PILOT, they discovered novel epigenetic drivers in pancreatic ductal adenocarcinoma, including PRMT1 in tumors that harbor KRAS mutations on the background of p53. KRAS and p53 are genes often associated with cancer.

“Through this assessment of epigenetic regulators, we identified PRMT1 as a top scoring ‘hit’ in these patient-derived tumors,” said Virginia Giuliani, PhD, Senior Research Scientist, IACS. “This novel dependency was subsequently validated in multiple patient-derived pancreas models.”

The team confirmed that genetic “knockdown” of PRMT1 significantly impaired pancreatic ductal adenocarcinoma cell growth in vitro through use of genetic editing tools, including CRISPR and small hairpin RNA (shRNA). This correlated with a global reduction in arginine methylation, which controls multiple cellular processes, including DNA replication and DNA repair.

“We also confirmed a role in pancreatic ductal adenocarcinoma tumor maintenance as inhibition of PRMT1 in patient-derived mouse models significantly inhibited tumor growth and extended survival,” said Dr. Giuliani. “These data suggest that small molecule inhibition of PRMT1 could be an impactful therapeutic strategy in pancreas cancer.”

The teams at MD Anderson’s and Center for Co-Clinical Trials are using the PILOT platform to investigate novel vulnerabilities across tumor subtypes with the aim of identifying targets for therapeutic development. PRMT1 is one of several epigenetic dependencies that have been identified using this approach.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


Advertisement

Advertisement



Advertisement