Potential Therapeutic Target Identified for Aggressive Pancreatic Cancer

Investigators have identified a novel protein called arginine methyltransferase 1 (PRMT1) that may serve as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC).

PDAC is the most common type of pancreatic cancer, with a 5-year survival rate of less than 10%. These poor outcomes further support the crucial need for identifying druggable targets essential for tumor maintenance.

In a new study, investigators developed an in vivo platform called Patient-based In vivo Lethality to Optimize Treatment (PILOT). The technology enables systemic identification of tumor vulnerabilities in patient-derived tumors.

The investigators used PILOT to identified novel epigenetic drivers in PDAC, including PRMT1, in tumors that harbor KRAS mutations on the background of p53—–two 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 senior investigator Virginia Giuliana, PhD. “This novel dependency was subsequently validated in multiple patient-derived pancreas models.”

The results of the study showed that a genetic “knockdown” of PRMT1 significantly impaired PDAC growth in vitro using genetic editing tools, including CRISPR and small hairpin RNA. The findings correlated with a global reduction in arginine methylation, which controls multiple cellular processes, including DNA replication and repair.

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

Currently, investigators at MD Anderson and Center for Co-Clinical Trials are using the PILOT platform to examine novel vulnerabilities across tumor subtypes, with a primary goal of identifying targets for therapeutic development. PRMT1 is 1 of several that have been identified using the PILOT approach.

The findings will be presented at the American Association for Cancer Research annual meeting, in Washington, DC.