Pancreatic cancer has become the third leading cause of cancer mortality. Its incidence is rising in parallel with the rise in obesity, and it’s hard to treat: five-year survival still hovers at just 8 to 9 percent. A new study published online in Nature Communications finds early success with a completely new, metabolic approach: reducing tumors’ ability to get rid of excess nitrogen.
The researchers, led by Nada Kalaany, PhD, of Boston Children’s Hospital’s Division of Endocrinology and the Broad Institute of MIT and Harvard, provide evidence that targeting the enzyme arginase 2 (ARG2) can curb pancreatic tumor growth, especially in people who are obese.
“We found that highly malignant pancreatic tumors are very dependent on the nitrogen metabolism pathway,” says Kalaany.
Curbing tumor growth by blocking nitrogen disposal
In this heatmap, red areas indicate higher expression of genes involved in nitrogen metabolism in human pancreatic tumors grown in obese mice versus lean mice. The differences were most statistically significant for ARG2. (Credit: Tamara Zaytouni, PhD)
The team began by introducing human pancreatic tumors into obese and lean mice. They then analyzed what genes the tumors turned on and what metabolic products they were producing.
To their surprise, that tumors in obese mice showed enhanced expression of many genes involved in metabolizing nitrogen, a natural byproduct of cells when proteins are broken down.
The effect was most pronounced for ARG2, an enzyme that helps dispose of excess nitrogen by breaking down ammonia, as part of the urea cycle.
Pancreatic tumors grew faster in obese mice than in lean mice and produced increased amounts of ARG2.
Through a collaboration with Massachusetts General Hospital and the Dana-Farber Cancer Institute, the researchers also analyzed tumor samples from 92 patients with pancreatic cancer. They showed that ARG2 levels in the tumors increased together with patients’ body mass index (BMI).
“Pancreatic tumors are known to take up and break down large amounts of protein to fuel their growth,” explains Kalaany, who is also an assistant professor at Harvard Medical School. “They need ARG2 to get rid of the extra nitrogen and prevent ammonia from accumulating.”
When the researchers silenced or deleted ARG2 in the tumors of obese mice, two things happened. Nitrogen accumulated (in the form of ammonia), and pancreatic cancer growth was strongly suppressed.
Not just the obese
Although pancreatic tumors grew more robustly in the obese mice and produced more ARG2 (as did tumors from higher-BMI patients), tumors in lean mice appear to activate the same metabolic pathway.
“In a lean mouse model bearing fast-growing tumors, we saw the same transcriptomic signature that we did in the obese mice,” says Kalaany. “It seems obesity or rapid growth exaggerate a tumor’s need to get rid of nitrogen.”
We found that highly malignant pancreatic tumors are very dependent on the nitrogen metabolism pathway.” ARG2 is closely related to ARG1, the liver enzyme we ourselves use to rid our bodies of excess nitrogen. Deficiency of ARG1 has been shown to cause neurological impairment, growth retardation and fatal ammonia toxicity in both mice and humans. But deleting the ARG2 gene does not appear to cause serious side effects, at least in mice.
“There could be a therapeutic window here,” says Kalaany.
The team now plans to conduct chemical screens to identify ARG2 inhibitors that could potentially be used as drugs. Most known inhibitors also inhibit ARG1, but at least one has action more specific to ARG2, she says.
“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 this work. “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.”
Tamara Zaytouni, PhD, of Boston Children’s, Harvard Medical School and the Broad Institute, was the paper’s first author. Other funding was provided by the Hirshberg Foundation for Pancreatic Cancer Research, a DFHCC SPORE in Gastrointestinal Cancer Developmental Project Award (P50CA127003), a Boston Children’s–Broad Institute Collaboration Grant, the V Foundation for Cancer Research and the American Diabetes Association.