Targeting Two Key Proteins to Weaken Pancreatic Cancer's Defenses

Indiana University School of Medicine scientists have identified a new way to weaken pancreatic cancer's defenses by targeting two key proteins that help the deadly disease resist treatment. The study, recently published in Redox Biology, revealed that a drug combination blocking the proteins together may offer a more effective strategy against pancreatic cancer and potentially other aggressive cancers.

With a five-year survival rate of just 13%, pancreatic cancer is one of the deadliest and most treatment-resistant cancers. In the study, researchers focused on redox effector factor-1 (Ref-1), a protein known to help tumor cells survive, and discovered that another protein - peroxiredoxin-1 (PRDX1) - reinforces its protective properties.

The scientists used a drug they developed called APX2014 to block Ref-1 in addition to removing PRDX1. Without the function of both proteins, tumors significantly shrank and more cancer cells died.

What really surprised us was how specific PRDX1 was in driving this effect. Among the entire family of related proteins, only loss of PRDX1 made tumors so much more sensitive to our Ref-1 drug. The combination worked better than either treatment alone, and in animal models, it resulted in smaller tumors and longer survival."

Mark Kelley, PhD, corresponding author of the study and the Betty and Earl Herr Professor of Pediatric Oncology Research at the IU School of Medicine

The findings also revealed that their approach affected tumor cells and their surrounding environment, highlighting the effectiveness of disrupting the tumor's support system as well as the cancer cells themselves.

The team of researchers from the Herman B Wells Center for Pediatric Research and IU Melvin and Bren Simon Comprehensive Cancer Center will continue to build on this discovery by testing new drugs that can target PRDX1 alongside Ref-1 inhibitors already in development. They also want to explore how this approach works in other cancers and move closer to designing clinical trials.

"This research shows us a brand new vulnerability in pancreatic cancer. By targeting both Ref-1 and PRDX1 together, we may be able to shut down the survival systems that make these tumors so hard to treat," said Melissa L. Fishel, PhD, co-author of the study, an associate professor of pediatrics and pharmacology and toxicology, and the Myles Brand Scholar in Cancer Research at the IU School of Medicine. "That opens the door to developing combination therapies that could work better than anything currently available, not just for pancreatic cancer but potentially for other aggressive cancers too."

Additional IU co-authors included Sonia Kiran, Randall S. Wireman, Jacqueline Peil, Dana K. Mitchell, Elizabeth Sierra Potchanant, Ratan Rai, Jonah Z. Vilseck, Sanya Haiaty and Millie M. Georgiadis.

This research was supported by funding from the National Institutes of Health and the Riley Children's Foundation.