Scientists have identified a new way to weaken pancreatic cancer’s defences 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 tumour 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, tumours 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 tumours so much more sensitive to our Ref-1 drug,” said Mark Kelley, PhD, corresponding author of the study and the Betty and Earl Herr Professor of Paediatric Oncology Research at the IU School of Medicine.

“The combination worked better than either treatment alone, and in animal models, it resulted in smaller tumours and longer survival.”

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

The team of researchers from the Herman B Wells Centre for Paediatric Research and IU Melvin and Bren Simon Comprehensive Cancer Centre 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 tumours so hard to treat,” said Melissa L. Fishel, PhD, co-author of the study, an associate professor of paediatrics 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.”

Article: The absence of Peroxiredoxin-1 in human pancreatic ductal adenocarcinoma (PDAC) markedly reduces cell survival and tumor growth when coupled with the inhibition of Ref-1 redox signaling

Source: Indiana University