Researchers at the University of Illinois Chicago (UIC) have created an experimental cancer treatment based on bacteria that live naturally inside tumors.
In preclinical studies involving prostate cancer, the therapy yielded surprising results when combined with radiation treatment. The approach stopped tumor growth by attacking 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 therapyaurB disrupted energy production within the tumor cells’ mitochondria, effectively depriving the tumors of the fuel they need to grow.
“Mitochondria are very important for a cell to survive; they are energy factories,” said Tohru Yamada, senior author of the study, an associate professor in the UIC departments of surgery and biomedical engineering and a member of the University of Illinois Cancer Center. “Many cancer cells have altered mitochondrial number and activity, because a cancer cell has to grow aggressively and rapidly. Therefore, mitochondria would be an ideal target for cancer therapy.”
Looking beyond the p53 gene
Scientists have known for years that tumors harbor communities of bacteria that exist within what is known as the tumor microenvironment. More recently, researchers have begun to explore whether such bacteria could provide compounds that could be developed into cancer treatments.
Previous work from Yamada’s lab identified a bacterial protein known as 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 in adults and in brain cancer studies in children.
However, the effectiveness of that peptide depends on a gene called p53. Because p53 is frequently mutated in cancer patients, and because those mutations vary from person to person, treatment may work well for some patients but not for others.
“We wanted to have an anticancer agent that did not use p53 function,” Yamada said.
Targeting cancer’s energy factories
To find an alternative approach, the researchers looked for a bacterial protein that acted through mitochondria rather than through 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 within the tumors. One bacterial species attracted special attention because it contained a cupredoxin protein known as auracyanin, which performs a similar function to the previously studied protein.
The researchers then designed an auracyanin-based peptide and named it aurB. Laboratory experiments revealed that aurB enters the mitochondria of tumor cells and binds to ATP synthase, a protein that plays a critical role in the generation of ATP, the main source of energy used by cells.
Strong results in prostate cancer models
The team evaluated aurB in cancer cell lines lacking active p53, as well as in mouse models of prostate cancer resistant to hormone therapy.
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 improved 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 preclinically demonstrated significant inhibition of tumor growth.”
Search for tumor bacteria for future anti-cancer drugs
The UIC has patented aurB with the collaboration of the university’s Technology Management Office. Researchers are now exploring opportunities to advance the therapy to human clinical trials.
At the same time, Yamada believes that auracyanin may represent just the beginning of a much bigger opportunity. Countless bacterial proteins remain unexplored and many could serve as the basis for future cancer therapies.
“There are many other bacterial proteins that could be sources of anti-cancer drugs,” Yamada said. “We just haven’t tried them yet.”
Yamada worked with collaborators from the School 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 success of the project.
Other UIC authors who participated in the study include Dr. Samer A. Naffouje, Duy Binh Tran, Konstantin Christov, Albert Green, Ngoc Hai Trieu Phong and Dr. Tapas K. Das Gupta of the Faculty of Medicine, along with Weiguo Li of the Faculty of Engineering.