City of Hope researchers combine engineered bacterium with enzyme to penetrate tumor defenses
DUARTE, Calif. — Patients with an aggressive form of pancreatic cancer known as pancreatic ductal adenocarcinoma currently have few good therapeutic options, with most medications able to increase survival by only a few months while exacting a high physical toll. City of Hope researchers appear to have found a better option, one that uses the Salmonella bacterium.
In a new study in the journal Cancer Immunology Research
, published by the American Association for Cancer Research, the researchers report that a specific bacterial-based therapy is able to home to tumors and provoke an extremely effective tumor-killing response. The study, conducted in preclinical mouse studies, found that the therapy frequently triggered the complete regression of pancreatic tumors and significantly extended survival.
“The results were, in a word, remarkable,” said lead researcher Don J. Diamond, Ph.D.,
who chairs the Department of Experimental Therapeutics
at City of Hope. “This method has the potential to treat a variety of cancers that share similar features to pancreatic ductal adenocarcinoma, currently one of the most difficult-to-treat cancers and one for which we desperately need better options.”
Bacteria-based therapies have been used to treat solid tumors for decades and are commonly used to treat bladder cancer, but the success of such therapies has been limited by many tumors’ defenses. In this new study, Diamond and his colleagues engineered the bacterium Salmonella typhimurium to crack those defenses.
The researchers did so by transforming the bacterium to carry a piece of DNA that targets a molecule known as IDO, which camouflages cancer cells and prevents the immune system from recognizing and killing the tumor. The modified bacterium, dubbed shIDO-ST, was combined with an enzyme (PEGPH20), provided to City of Hope by Halozyme Therapeutics, that digests hyaluronan. Hyaluronan acts as a physical barrier to prevent drugs from reaching tumor cells.
When tumors were first pretreated with PEGPH20, the researchers found that the modified bacteria penetrated them much more effectively.
“The therapy is able to completely cure tumors in mice,” said Edwin R. Manuel, Ph.D.
, a staff scientist in the Department of Experimental Therapeutics at City of Hope and first author on the new study. “In two models of pancreatic cancer, the tumor regressed in the majority of animals. We observed the mice for a year or more, and the cancer did not return.”
Diamond, Manuel and their colleagues now aim to tease apart the molecular mechanisms underlying these processes, with the goal of making the treatment even more effective and adaptable to many other cancers.
“We think this therapy has applications not just to pancreatic cancer, but to a whole slew of other cancers,” said Diamond. “About 50 percent of all solid tumors have an involvement with IDO and hyaluronan, including prostate, breast and ovarian cancers.”
The researchers are also in the process of developing the approach in order to translate it into the clinic. “We’ve made great strides toward bringing this therapy into clinical trials,” Diamond said.
About City of Hope
City of Hope is an independent research and treatment center for cancer, diabetes and other life-threatening diseases. Designated as a comprehensive cancer center, the highest recognition bestowed by the National Cancer Institute, City of Hope is also a founding member of the National Comprehensive Cancer Network, with research and treatment protocols that advance care throughout the nation. City of Hope’s main hospital is located in Duarte, California, just northeast of Los Angeles, with clinics in Southern California. It is ranked as one of “America’s Best Hospitals” in cancer by U.S. News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation and genetics.
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