New Protein Discovery Offers Hope for Treating Aggressive Cancers

Researchers at the Indiana University School of Medicine have made a significant breakthrough in understanding pancreatic cancer, which could lead to more effective treatments. By targeting the protective role of two specific proteins, scientists have unveiled a new vulnerability in pancreatic ductal adenocarcinoma (PDAC), the most prevalent form of pancreatic cancer. This cancer type has a notoriously low overall survival rate of around 13% and is intrinsically resistant to most treatment options, including chemotherapy and immunotherapy.

The study, led by Melissa Fishel, PhD, a tumor cell biologist, focused on two proteins: redox effector factor-1 (Ref-1) and peroxiredoxin-1 (PRDX1). Both proteins are found in higher concentrations in pancreatic tumors compared to normal tissues and work together to enhance resistance to treatment. “This research shows us a brand new vulnerability in pancreatic cancer,” said Fishel. “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.”

The researchers employed advanced techniques, including CRISPR/Cas9 gene editing, to reduce PRDX1 expression in pancreatic cancer cells. They then treated these cells with the drug APX2014, which inhibits Ref-1’s activity. The approach was evaluated using various models, including cell cultures, 3D co-culture systems, and mice implanted with human tumor cells.

In their findings, the team discovered that when Ref-1 was inhibited, PRDX1 became essential for cancer cell survival. Removing PRDX1 significantly increased the sensitivity of pancreatic cancer cells to APX2014, leading to enhanced cell death. The study revealed that in co-culture models, which included cancer-associated fibroblasts (CAFs), the combination of PRDX1 depletion and APX2014 treatment disrupted both tumor and stromal cell survival.

CAFs play a crucial role in pancreatic cancer by forming a protective stroma that hinders drug penetration. These cells communicate with tumor cells, promoting growth and resistance to treatment. The study indicated that both the tumor cells and CAFs rely on redox proteins like PRDX1 and Ref-1, establishing a chemical partnership that aids their survival in the harsh tumor environment.

Animal models treated with APX2014 and bearing PRDX1-knockout tumors exhibited smaller tumors and improved survival rates. Patient tumor samples also showed elevated levels of both Ref-1 and PRDX1 compared to normal tissues, highlighting the clinical relevance of these findings.

“What really surprised us was how specific PRDX1 was in driving this effect,” noted Mark Kelley, PhD, the study’s corresponding author and a professor of pediatric cancer research. “The combination worked better than either treatment alone, and in animal models, it resulted in smaller tumors and longer survival.”

Despite the promising results, the study does have limitations. Much of the data comes from laboratory-grown cells and mouse models, and human trials will be necessary to validate these findings. Additionally, while APX2014 was directly injected into tumors in mice, clinical applications will likely require different delivery methods, such as oral or intravenous administration.

Nevertheless, the findings suggest that dual targeting of Ref-1 and PRDX1 could provide a novel approach to overcoming drug resistance in pancreatic cancer. Given that other cancers also depend on oxidative signaling pathways, this strategy might extend to treating various aggressive cancer types.

The potential for accelerated clinical application is noteworthy, as a related drug, APX3330, is already available in oral form and is undergoing trials in humans. This development raises the possibility of quickly translating laboratory discoveries into viable treatment options for patients.

The study’s results were published in the journal Redox Biology, marking a significant step forward in the quest for more effective treatments for one of the deadliest forms of cancer.