Enzyme Target Shows Promise as Pancreatic Cancer Therapy

Pancreatic cancer—the third leading cause of cancer-related deaths—with incidence rates that mirror the increase in obesity. The survival rate for pancreatic cancer is only 8% or 9%, highlighting the need for new treatment options.

Targeting an enzyme that tumors harness to dispose of nitrogen has shown promise as a novel approach to treating pancreatic cancer, according to a study published by Nature Communications.

The study suggests that targeting the arginase 2 (ARG2) enzyme can inhibit the growth of pancreatic tumors. These findings were especially prominent in obese patients, according to the authors.

The investigators introduced human pancreatic tumors into obese and lean mice and investigated which genes the tumors turned on and which metabolic products they created, according to the study.

The authors discovered that tumors in obese mice had increased expression of genes involved with metabolizing nitrogen. It has been previously unknown how excess nitrogen affects tumors.

"We found that highly malignant pancreatic tumors are very dependent on the nitrogen metabolism pathway," said lead researcher Nada Kalaany, PhD.

Pancreatic tumors were observed to grow faster in obese mice compared with lean mice. The authors also noted that the obese mice had increased production of the enzyme ARG2, which helps rid the body of excess nitrogen by breaking it down to ammonia and releasing it in urine, according to the study.

The investigators also assessed tumor samples from 92 human patients with pancreatic cancer and found ARG2 levels increased with body mass index (BMI).

When ARG2 was silenced or deleted in the tumors of obese mice, nitrogen accumulation and pancreatic cancer growth was reduced, according to the study.

"Pancreatic tumors are known to take up and break down large amounts of protein to fuel their growth," Dr Kalaany said. "They need ARG2 to get rid of the extra nitrogen and prevent ammonia from accumulating."

While pancreatic tumors grew more rapidly in obese mice and created more ARG2, similar to the findings in patients with high BMI, lean mice were observed to have the same pathway.

"In a lean mouse model bearing fast-growing tumors, we saw the same transcriptomic signature that we did in the obese mice," Dr Kalaany said. "It seems obesity or rapid growth exaggerate a tumor's need to get rid of nitrogen."

ARG2 is highly similar to ARG1, the liver enzyme humans use to rid the body of excess nitrogen. In both mice and humans, ARG1 deficiencies have been observed to result in neurological impairment, growth retardation, and fatal ammonia toxicity, according to the study.

However, deleting ARG2 in mice was not observed to cause serious adverse events.

"There could be a therapeutic window here," Dr Kalaany said.

The investigators plan to screen chemicals to discover inhibitors of ARG2 that could be used as a compound against pancreatic cancer. Currently, many inhibitors also affect ARG1, but the investigators expect there will be at least 1 that has more specific effects on ARG2, according to the study.

"Pancreatic cancer is notoriously resistant to conventional treatment options," said Julie Fleshman, JD, MBA, president and CEO at the Pancreatic Cancer Action Network, which helped fund the study. "The discovery of novel drug targets like ARG2 could have a significant impact on patient outcomes and move us closer to our goal to double pancreatic cancer survival by 2020."