Nitrogen-clearing enzyme a new target for difficult-to-treat pancreatic cancers

Human tumor cells from the pancreas
Pancreatic cancer is difficult to treat because of the organ's location deep in the body. Attacking tumor metabolism is one way to get around this hurdle.

While pancreatic cancer is relatively rare in the U.S., it's also difficult to treat and often deadly. Now researchers at Boston Children’s Hospital are working to cripple the ability of pancreatic tumors to grow by altering their metabolism.

The Boston Children’s team targeted the enzyme arginase 2 (ARG2), which tumors use to clear the excess nitrogen that's produced when they break down protein. “They need ARG2 to get rid of the extra nitrogen and prevent ammonia from accumulating,” explained Nada Kalaany, an associate professor in pediatrics at Harvard Medical School, who led the research, in a statement.

The team put human pancreatic tumors in obese and lean mice and observed that the tumors grew more quickly and produced more ARG2 in obese mice. They also looked at tumor samples from 92 patients with pancreatic cancer and found that ARG2 levels rose as patients’ body mass index increased.

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The tumors in the obese mice had “enhanced” expression of genes that play a role in metabolizing nitrogen. The role of nitrogen metabolism in tumors has previously been unknown. The findings are published in Nature Communications.

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Removing the enzyme from the tumors of obese mice “strongly” curbed tumor growth. While obese mice had more aggressive tumors with higher amounts of ARG2, fast-growing tumors in lean mice seem to use the same metabolic pathway. “There could be a therapeutic window here,” Kalaany said.

Pancreatic cancer is usually treated with intravenous chemotherapy, but these injections tend to fail due to the pancreas’s location deep in the abdomen. Targeting a tumor’s metabolism would leapfrog this obstacle. Scientists at the University of Texas Southwestern Medical Center found that CDK4/6 inhibitors made the metabolism of pancreatic tumors more active, in addition to suppressing their growth. This disrupted metabolism could be targeted by other drugs, such as mTOR inhibitors, which act on enzymes that regulate metabolism.

The next step for Boston Children's is to identify ARG2 inhibitors that could become drugs to treat pancreatic cancer. But they have to make sure those agents don’t also affect ARG1, a related enzyme that the human liver uses to clear excess nitrogen. ARG1 deficiency can cause serious problems, such as neurological impairment or a lethal buildup of ammonia.