In preclinical studies involving prostate cancer, the therapy delivered striking results when paired with radiation treatment. The approach halted tumor growth by targeting the cancer cells' energy supply. The treatment is built from a small fragment of a bacterial protein called aurB. According to findings published in the journal Signal Transduction and Targeted Therapy, aurB disrupted energy production within tumor cell mitochondria, effectively depriving tumors of the fuel they need to grow.

"The mitochondria are very important for a cell to survive; they are the energy factories," said Tohru Yamada, senior author of the study, associate professor in the departments of surgery and biomedical engineering at UIC and a member of the University of Illinois Cancer Center. "Many cancer cells exhibit altered mitochondrial number and activity, because a cancer cell has to grow aggressively and rapidly. Therefore, the mitochondria would be an ideal target for cancer therapy."

Looking Beyond the p53 Gene

Scientists have known for years that tumors are home to communities of bacteria that exist within what is known as the tumor microenvironment. More recently, researchers have begun exploring whether those bacteria might provide compounds that can be turned into cancer treatments.

Earlier work by Yamada's laboratory identified a bacterial protein known as a cupredoxin that could suppress tumor growth. Cupredoxins are copper-containing proteins that help transfer electrons between other proteins.

Based on that discovery, the team developed a peptide drug and tested it extensively, including in clinical trials involving adults and in studies of brain cancer in children.

However, the effectiveness of that peptide relies on a gene called p53. Because p53 is frequently mutated in cancer patients, and because those mutations vary from person to person, the treatment may work well for some patients but not others.

"We wanted to have an anti-cancer agent that doesn't use the p53 function," Yamada said.

Targeting Cancer's Energy Factories

To find an alternative approach, the researchers searched for a bacterial protein that acts through the mitochondria rather than the p53 pathway. Their search led them to another cupredoxin protein.

For the new study, the team analyzed tumor samples from breast cancer patients and used DNA sequencing to identify the bacteria present inside the tumors. One bacterial species attracted particular attention because it contained a cupredoxin protein known as auracyanin, which performs a function similar to the protein studied previously.

The researchers then designed a peptide based on auracyanin and named it aurB. Laboratory experiments revealed that aurB enters tumor cell mitochondria and attaches to ATP synthase, a protein that plays a critical role in generating ATP, the primary energy source used by cells.

Strong Results in Prostate Cancer Models

The team evaluated aurB in cancer cell lines lacking active p53 as well as mouse models of hormone therapy-resistant prostate cancer.

When combined with radiation therapy, one of the standard treatments for prostate cancer, aurB produced a substantial reduction in tumor growth without signs of significant toxicity.

"The combination significantly enhanced the activity of the peptide and the tumor became much smaller," Yamada said. "This approach is promising. Using a well-established tibial bone metastatic model, we demonstrated significant inhibition of tumor growth, preclinically."

Searching Tumor Bacteria for Future Cancer Drugs

UIC has patented aurB with assistance from the university's Office of Technology Management. The researchers are now exploring opportunities to advance the therapy into human clinical trials.

At the same time, Yamada believes auracyanin may represent only the beginning of a much larger opportunity. Countless bacterial proteins remain unexplored, and many could potentially serve as the foundation for future cancer therapies.

"There are many other bacterial proteins that could be source of cancer drugs," Yamada said. "We simply haven't tried them yet."

Yamada worked with collaborators from the College of Medicine and UI Health and credited the Department of Surgery, including Drs. Martin Borhani, Aslam Ejaz, Ajay Rana, Enrico Benedetti and Tapas K. Das Gupta, whose contributions played a key role in the project's success.

Additional UIC authors on the study include Dr. Samer A. Naffouje, Duy Binh Tran, Konstantin Christov, Albert Green, Ngoc Hai Trieu Phong and Dr. Tapas K. Das Gupta from the College of Medicine, along with Weiguo Li from the College of Engineering.