BUFFALO, N.Y.,Apr 25: A preclinical study published in Nature Metabolism reveals that impaired functioning of two key enzymes contributes to the development and progression of precancerous lesions in the pancreas — a finding that could pave the way for prevention and earlier detection of one of the deadliest cancer types. The work is based on the postdoctoral research of first author Megan Radyk, PhD, Assistant Professor of Oncology, Department of Pharmacology & Therapeutics at Roswell Park Comprehensive Cancer Center.
While most cancer research focuses on established tumors, less emphasis has been placed on precancers, notes Dr. Radyk, who conducted the research when she was a postdoctoral research fellow at the University of Michigan.
“Precancer and established cancers look and behave very differently,” she says. “My research interest lies in figuring out, years before we see evidence of a tumor, what actually goes wrong in the cells that allows a precancer to progress, and how we can intercept some of those changes.”
The research was performed in the lab using preclinical models with mutations in the KRAS gene, which are present in 90-95% of pancreatic cancers. The team found that more precancerous lesions were found in models that had mutant KRAS and reduced function in two enzymes, glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1).
Both G6PD and ME1 produce the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), which enables cells to reduce levels of reactive oxygen species (ROS). ROS, which contribute to the development of precancerous lesions, were higher in pancreatic cells that had lower levels of G6PD and ME1.
While more precancerous lesions were observed in preclinical models with reduced ME1 or G6PD activity, cancer progression did not appear to be affected. With reduced G6PD activity, precancerous lesions did not progress to cancer; however, pancreatic cancer developed with reduced ME1 activity.
Dr. Radyk and her colleagues, who included co-senior authors from the University of Michigan, Henry Ford Health System and Michigan State University, also found that precancerous lesions could be prevented with antioxidants, suggesting a possible therapeutic strategy.
Few early-detection methods exist for pancreatic cancer, which is usually discovered in the advanced stages, when most treatments are ineffective.
“This richer understanding of the metabolic changes that take place in precancerous lesions could help us identify biomarkers to gauge a patient’s cancer risk and diagnose the disease earlier and could point the way to dietary measures for suppressing some cancers early in their development,” notes Dr. Radyk.
