Battling with bacteria

DUARTE, Calif.—While much ado has been made about the healthy bacteria in our microbiome and their importance to our health, bacteria aren't generally thought of as health aides. But in light of some recent work from City of Hope scientists, that might be changing.

While bacteria-based therapies have been in use for years—consisting of a weakened form of the microbe used as either the therapy itself or as a delivery vector to induce anti-tumor responses only at the cancer site—their success has been mixed. Such therapies are a common tool in treating bladder cancer, but when researchers have tried to use Salmonella typhimurium (ST) against melanoma or renal tumors, the bacteria reached the tumors without issue, but failed to do much once they got there.

The team at City of Hope tried another subset of cancer entirely, a particularly aggressive form of pancreatic cancer known as pancreatic ductal adenocarcinoma (PDAC), and detailed their results in a paper titled “Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors,” which appeared in Cancer Immunology Research, published by the American Association for Cancer Research. PDAC is “often inoperable and is only transiently responsive to existing therapies,” according to the City of Hope website.

The researchers, led by Dr. Don J. Diamond, chair of the Department of Experimental Therapeutics at City of Hope, had to modify the bacterium to see success, as unmodified ST failed to affect the cancer cells. Pancreatic cancer cells secrete a thick barrier of hyaluronan, a sugary molecule that blocks drugs from reaching tumor cells, in addition to producing a large amount of indoleamine 2, 3-dioxygenase (IDO), a potent immunosuppressive molecule that camouflages cancer cells to hide them from the immune system.

To overcome these issues, the team transformed bacteria to bear a piece of DNA that encodes a molecule that can block IDO, known as small hairpin RNA-IDO, or shIDO. The modified strain of ST, referred to as shIDO-ST, was then combined with the enzyme PEGPH20, which digest hyaluronan. PEGPH20 was provided by Halozyme Therapeutics for the study.

On a City of Hope webpage detailing Diamond's current projects, it's noted that “ST as an shRNA delivery vehicle offers superior penetration against desmoplastic PDAC tissue, and anti-metastatic function due to its motility and affinity for poorly vascularized, hypoxic tumor tissue. The combination of IDO silencing and abundant ST tumor colonization increases intratumoral concentrations of reactive oxygen species through the recruitment and activation of polymorphonuclear neutrophils (PMN), which can cause oxidative stress-induced apoptosis of tumor cells, cancer stem cells and vascular stroma to inhibit PDAC progression. PMN are also known to have anti-metastatic function, thus providing additional protection against tumor spread.”

In an animal model with transplanted pancreatic tumors, tumor size decreased in all tested animals, and in two-thirds of cases, the treated animals even showed a complete regression of their tumors. Complete regression and extended survival were also seen in a second model in which tumors spontaneously formed, similar to human disease.

“The therapy is able to completely cure tumors in mice,” commented Dr. Edwin R. Manuel, 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.”

“We think this therapy has applications not just in pancreatic cancers, but in a whole slew of other cancers,” Diamond added in a press release. “About 50 percent of all solid tumors have an involvement with IDO and hyaluronan, including prostate, breast and ovarian cancers.”

As they continue pursuing this approach, the team wants to investigate the molecular mechanisms behind this therapy's effectiveness in overcoming the tumor cells' defenses. Additionally, they are also working to develop this method for translation into the clinic.

There is a great need for new, effective therapies for pancreatic cancer. This cancer type hasn't seen any significant improvement in outlook or survival rates in the last 25 years, and according to a 2014 study, the next 15 years might not be any brighter. The Cancer Research piece, “Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States,” estimates that pancreas and liver cancers “are projected to surpass breast, prostate and colorectal cancers to become the second and third leading causes of cancer-related death by 2030, respectively.”

The American Cancer Society estimates that there will be 48,960 new cases of pancreatic cancer diagnosed in the United States this year, with 40,560 deaths due to the disease, which generally affects men and women in equal proportions.