UIC scientists source anti-cancer treatment in bacteria

Researchers at the University of Illinois Chicago have developed an anti-cancer therapy inspired by bacteria found in cancer tumors.

When tested in combination with radiation in animal models of prostate cancer, it was highly effective - the approach effectively shut down tumor growth. The therapy is made from a fragment of a bacterial protein, a peptide called aurB. In cancer tumors in the animal models, aurB prevented energy production in the tumor cells' mitochondria, essentially cutting off the tumor's fuel, the researchers report in the journal Signal Transduction and Targeted Therapy.

"The mitochondria are very important for a cell to survive; they are the energy factories," said Tohru Yamada, senior author on 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."

From p53 to the mitochondria

Scientists have long known that bacteria live in tumors in a milieu known as the tumor microenvironment. But over the last few decades, researchers have started looking to these bacteria as potential sources of anti-tumor agents.

In previous studies, Yamada and his lab found that a bacterial protein called a cupredoxin effectively suppressed tumors. Cupredoxins are a group of copper-containing proteins that transport electrons between other proteins.

The team created a peptide drug based on the protein and tested it thoroughly, in human adult clinical trials and on brain cancer in children.

But that peptide's efficacy depends on a gene called p53, Yamada said. P53 is a tumor-suppressor gene that is mutated in many cancer patients, though the mutations are not all the same. That means the anti-tumor peptide could work on some mutations, but not others.

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

Powerful preclinical results

So the researchers went looking for a bacterial protein that instead works via the mitochondria, those all-important cellular energy factories. And they found it in another cupredoxin.

In their new study, Yamada and colleagues first took tumor samples from patients with breast cancer and identified the bacteria residing in them with DNA sequencing. One bacterium stood out; it contained a cupredoxin protein called auracyanin, which has a similar function to the one from the previous study.

The researchers created a peptide drug mimicking auracyanin, which they named aurB. Molecular experiments showed that aurB works by entering tumor cells' mitochondria and binding to ATP synthase, critical for producing the cellular energy source ATP.

They then tested it in p53-inactive cell lines and mouse models of hormone therapy-resistant prostate cancer. When combined with radiation, which is one of the standard treatment options for prostate cancer, aurB significantly decreased tumor growth without apparent 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."

Expanding the search to new bacteria

The team has patented aurB with guidance from UIC's Office of Technology Management. Next, they will explore avenues for clinical trials to test the treatment in humans.

In the meantime, Yamada continues to look to bacteria for drug-design inspiration. Auracyanin, he said, is likely just one of countless bacterial proteins waiting to be discovered and manipulated in a similar way.

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

Yamada partnered with colleagues across 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 were central to the project's success.

Other UIC authors of 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 and Weiguo Li from the College of Engineering.