A metabolic treatment for pancreatic cancer?

August 15, 2017, Children's Hospital Boston
Axial CT image with i.v. contrast. Macrocystic adenocarcinoma of the pancreatic head. Credit: public domain

Pancreatic cancer is now the third leading cause of cancer mortality. Its incidence is increasing in parallel with the population increase in obesity, and its five-year survival rate still hovers at just 8 to 9 percent. Research led by Nada Kalaany, PhD, at Boston Children's Hospital and the Broad Institute of MIT and Harvard, now suggests a novel approach to treating this deadly cancer: targeting an enzyme that tumors use to get rid of nitrogen.

The study, published online today in Nature Communications, provides evidence that targeting the enzyme arginase 2 (ARG2) can curb the growth of pancreatic tumors, especially in people who are obese.

The researchers 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. They found that tumors in obese mice had enhanced expression of many genes involved in metabolizing , a natural byproduct of cells when proteins are broken down.

Until now, how nitrogen excess affects growth has been largely unknown.

"We found that highly malignant pancreatic tumors are very dependent on the nitrogen metabolism pathway," says Kalaany, a researcher in Boston Children's Division of Endocrinology and an assistant professor at Harvard Medical School.

Curbing tumor growth by preventing nitrogen disposal

Pancreatic tumors grew faster in obese mice than in lean mice and produced increased amounts of ARG2, an enzyme that helps dispose of excess nitrogen by breaking down ammonia, as part of the urea cycle.

Kalaany and colleagues also analyzed tumor samples removed from 92 patients with pancreatic , through collaboration with Massachusetts General Hospital and the Dana-Farber Cancer Institute. They showed that ARG2 levels in the tumors increased together with patients' body mass index (BMI).

When the researchers silenced or deleted ARG2 in the tumors of obese mice, nitrogen accumulated (in the form of ammonia) and cancer growth was strongly suppressed.

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

Not just the obese

Although 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 ," says Kalaany. "It seems obesity or rapid growth exaggerate a tumor's need to get rid of nitrogen."

ARG2 is closely related to ARG1, the liver enzyme we ourselves use to rid our bodies of . In mouse models and in humans, deficiencies of ARG1 have been shown to cause neurological impairment, growth retardation and fatal ammonia toxicity. But deleting the ARG2 gene does not appear to cause serious side effects, at least in .

"There could be a therapeutic window here," says Kalaany. The team plans to conduct chemical screens to identify inhibitors of arginase 2 that could potentially be used as drugs. Most known inhibitors also inhibit arginase 1, but at least one has action more specific to arginase 2, 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 survival by 2020."

Explore further: Study pinpoints gene's role in pancreatic cancer

Related Stories

Study pinpoints gene's role in pancreatic cancer

August 11, 2017
Pancreatic cancer is a particularly deadly form of disease, and patients have few options for effective treatment. But a new Yale-led study has identified a gene that is critical to pancreatic cancer cell growth, revealing ...

Researchers find novel way to induce pancreatic cancer cell death

April 10, 2017
Pancreatic cancer, most frequently pancreatic ductal adenocarcinoma (PDAC), is the most lethal and aggressive of all cancers. Unfortunately, there are not many effective therapies available other than surgery, and that is ...

Study reaffirms the belief that malignant cell behavior is influenced by the tumor tissue of origin

September 9, 2016
(Medical Xpress)—A team of researchers affiliated with several institutions in the U.S. has conducted a study of cancer in mice and found evidence that reaffirms results from prior research suggesting that malignant cell ...

Starving pancreatic cancer cells: Scientists identify potential pancreatic cancer target

October 17, 2016
Researchers have found that a protein called SLC6A14 is overexpressed by several fold in pancreatic tumors taken from patients and in cancerous pancreatic cells lines compared with normal pancreatic tissue or normal pancreatic ...

Scientists find potential loophole in pancreatic cancer defenses

March 27, 2013
Dana-Farber Cancer Institute scientists and colleagues have discovered that pancreatic cancer cells' growth and spread are fueled by an unusual metabolic pathway that someday might be blocked with targeted drugs to control ...

Recommended for you

Combining three treatment strategies may significantly improve melanoma treatment

December 12, 2018
A study by a team led by a Massachusetts General Hospital (MGH) investigator finds evidence that combining three advanced treatment strategies for malignant melanoma—molecular targeted therapy, immune checkpoint blockade ...

Lethal combination: Drug cocktail turns off the juice to cancer cells

December 12, 2018
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth—this was discovered by researchers from the University of Basel's Biozentrum two years ago. In a follow-up study, ...

An integrated approach to finding new treatments for breast cancer

December 12, 2018
Unraveling the complexity of cancer biology can lead to the identification new molecules involved in breast cancer and prompt new avenues for drug development. And proteogenomics, an integrated, multipronged approach, seems ...

Researchers use computer model to predict prostate cancer progression

December 12, 2018
An international team of cancer researchers from Denmark and Germany have used cancer patient data to develop a computer model that can predict the progression of prostate cancer. The model is currently being implemented ...

New insight into stem cell behaviour highlights therapeutic target for cancer treatment

December 12, 2018
Research led by the University of Plymouth and Technische Universität Dresden has identified a new therapeutic target for cancer treatment and tissue regeneration – a protein called Prominin-1.

Pushing closer to a new cancer-fighting strategy

December 11, 2018
A molecular pathway that's frequently mutated in many different forms of cancer becomes active when cells push parts of their membranes outward into bulging protrusions, Johns Hopkins researchers report in a new study. The ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.