Wake Forest University School of Medicine scientists uncover cancer treatment strategy that pushes tumor cells past their breaking point 

WINSTON-SALEM, N.C., Nov. 4, 2025 — Scientists at Wake Forest University School of Medicine have discovered a new way to kill cancer cells by blocking their ability to clean up harmful waste. Cancer cells produce high levels of hydrogen peroxide, which can damage them if it builds up. Normally, they rely on a special protein to keep this in check. The research team found a way to shut down that protein, causing toxic levels of hydrogen peroxide to overwhelm the cancer cells and destroy them, according to a study published in Science Advances. 

“We all make hydrogen peroxide all the time, but cancer cells make more,” said W. Todd Lowther, Ph.D., professor of biochemistry at Wake Forest University School of Medicine and the study’s corresponding author. “If we inhibit peroxiredoxin-3, the hydrogen peroxide levels go even higher and kill the cancer cells. It’s kind of like pushing them off a cliff.” 

Peroxiredoxin-3 (PRX3), which acts like a cleanup crew inside cancer cells, sits inside mitochondria and breaks down hydrogen peroxide before it becomes toxic. Tumor cells turn up PRX3 and other antioxidant defenses to handle the stress created by their altered metabolism. 

Most people think of antioxidants as protective. It turns out cancer cells do, too. 

The research team based their work on thiostrepton, a natural product with anticancer properties. Lowther’s team, which includes biochemist Kimberly J. Nelson, Ph.D., and medicinal chemist Terrence L. Smalley Jr., Ph.D., took the molecule apart, piece by piece, until they found the smallest fragment that still did the job. 

The team discovered a tiny piece of the compound that can attach to a protein called PRX3 and switch it off. PRX3 normally helps cancer cells clean up harmful molecules. When it’s turned off, those molecules, like hydrogen peroxide, build up so much that the cancer cells can’t survive.  

“Thiostrepton is a really big and bulky compound, and it’s not very soluble,” Lowther said. “Ultimately, our goal is to be able to treat any kind of cancer, and typically, you would do that using a chemotherapy drug where you deliver it into the bloodstream through an IV infusion. But you can’t do that with thiostrepton.” 

Mesothelioma, a rare and aggressive cancer often diagnosed at advanced stages, is one example where current treatment options are limited, and patients frequently face poor long-term outcomes. Thiostrepton is already being tested in mesothelioma through direct lung delivery, but its size restricts broader use. The smaller fragment represents a new opportunity to deliver a treatment intravenously and reach cancers throughout the body. 

The smaller fragment, called WF-242, killed cancer cells as effectively as thiostrepton while avoiding many of the unwanted interactions seen with the parent molecule. 

“The exciting part was identifying the minimal fragment and then confirming that it did not have what are called off-target effects like the intact thiostrepton molecule,” Lowther said. “That increases specificity and has the potential for fewer side effects.” 

Using cell-based studies, the team showed that WF-242 can kill cells from ovarian, lung, brain, prostate and blood cancers. Instead of lowering oxidative stress in tumors, this strategy deliberately increases it. Because cancer cells already operate near their limit for handling hydrogen peroxide, they’re more vulnerable to this approach than normal cells. 

“We’ve tested the compounds across many cancer types, and it appears to be working,” Lowther said.  

To make the new compound better, the team used a technique called X-ray crystallography to see exactly how the fragment connects to the protein that helps cancer cells survive. 

“For me, it’s always exciting to see the structure of how a drug binds to its target,” Lowther said. “It gives us insight into how to improve the drug.” 

The researchers are now refining the fragment to improve stability and solubility, work that typically takes three to five years before a candidate is ready for clinical testing. 

If successful in clinical trials, the approach could provide treatment options for cancers that currently have limited therapies. 

The work was funded by the Wake Forest Innovations Catalyst Fund, the Atrium Health Wake Forest Baptist Comprehensive Cancer Center, and the Center for Redox Biology and Medicine. 

Wake Forest University School of Medicine, the academic core of Advocate Health, advances cancer care through more than 1,000 clinical trials nationwide. At the heart of this work is the NCI-designated Comprehensive Cancer Center at Atrium Health Wake Forest Baptist, where members lead research and innovation as a cornerstone of progress for over 50 years.