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Copycat nutrient leaves pancreatic tumors starving, may inform cancer treatment

Copycat nutrient leaves pancreatic tumors starving, may inform cancer treatment
Broadly inhibiting glutamine metabolism with DON suppresses PDAC tumor growth. a, Growth of syngeneic KPC tumors implanted subcutaneously and treated with vehicle control (Ctrl) or DON (10 mg kg−1) for 2 weeks. Tumor volumes were measured with a digital caliper at the indicated time points. Data are presented as the mean ± s.e.m. of n = 4 mice per eight tumors per group. Day 18, P = 0.0016; day 21, P = 0.0007; days 23, 25 and 28, P < 0.0001. b, Weights of KPC orthotopic tumors from animals treated with Ctrl or DON for 10 days. Representative tumor images are shown. Data are presented as the mean ± s.e.m. of n = 8 or n = 9 mice per group (Ctrl, DON). P = 0.0003. c, Weights of PaTu 8988T orthotopic tumors from animals treated with Ctrl or DON for 3 weeks. Representative tumor images are shown. Data are presented as the mean ± s.e.m. of n = 7 mice per group. P = 0.0009. d, Weights of 779E orthotopic tumors from animals treated with Ctrl or DON for 2 weeks. Representative tumor images are shown. Data are presented as the mean ± s.e.m. of n = 8 or n = 7 mice per group (Ctrl, DON). P = 0.001. e, Immunohistochemical staining of proliferation markers pHis-H3 and Ki-67 in KPC orthotopic tumors treated with Ctrl or DON. Representative images are shown. Scale bars, 100 µm. f, Quantification of pHis-H3- or Ki-67-positive nuclei per image field, shown as the mean ± s.e.m. of n = 4 tumors per group. pHis-H3, P = 0.0319; Ki-67, P = 0.0227. Statistical significance was calculated using unpaired two-tailed Student's t-test (a–d and f). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Credit: Nature Cancer (2023). DOI: 10.1038/s43018-023-00649-1

A study led by scientists at Sanford Burnham Prebys suggests an entirely new approach to treat pancreatic cancer. The research shows that feeding tumors a copycat of an important nutrient starves them of the fuel they need to survive and grow. The method, described in the journal Nature Cancer, has been used in early clinical trials for lung cancer. However, the unique properties of pancreatic cancer may make the strategy an even stronger candidate in the pancreas.

"Pancreatic relies on the nutrient much more than other cancers, so therapies that can interfere with tumors' ability to access glutamine could be highly effective," says senior author Cosimo Commisso, Ph.D., director and associate professor of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys.

Pancreatic cancer is relatively rare, accounting for only 3% of all cancers. However, it has one of the lowest among cancers: most people only live three to six months after being diagnosed with this disease.

"Over the course of the past decade, there has been a notable improvement in survival rates for pancreatic cancer, but they still hover around just 10%," says Commisso. "There is a dire need for new treatments for these cancers."

One of the challenges of treating pancreatic cancer has to do with the physical properties of the tumors themselves.

"Pancreatic tumors tend to be packed in dense connective tissue that keeps them encapsulated from the rest of the body and cuts off their supply of oxygen," says Commisso. "As a consequence, these cancers develop unique metabolic properties compared to other tumors, and this is something we may be able to exploit with new treatments."

One of the metabolic quirks of pancreatic cancer is that it relies heavily on glutamine to produce energy for growth and survival. In the past, scientists have tried to block access to glutamine to slow the growth of pancreatic tumors, but this is easier said than done.

The new method relies on a molecule called DON that has structural similarities to glutamine but can't actually be used as a nutrient source. By studying mice, the research team found that DON significantly slowed pancreatic growth and stopped the tumors from spreading.

Although DON was able to stop pancreatic tumors from using glutamine, pancreatic can use other nutrients to grow in glutamine's absence. To combat this effect, the researchers combined DON with an existing cancer treatment that blocks the metabolism of asparagine, another important nutrient. The combined treatment had a synergistic effect, helping prevent the spread of pancreatic tumors to other distant organs, such as the liver and lungs.

"With DON, the cancer cells can't use glutamine, but they can start to depend on other nutrients as a backup, including asparagine," says Commisso. "We thought that if we could stop them from using glutamine and asparagine, the tumors would run out of options."

Although this is the first time this combination of treatments has been proposed for any cancer, the approach of using DON on its own has already advanced to early clinical trials in .

"This is particularly exciting, because exploring it further for pancreatic cancer patients could be relatively simple, since the study designs exist for other solid tumors," adds Commisso. "This could be a game changer for , and a lot of the preclinical work needed to rationalize it is already happening."

More information: Maria Victoria Recouvreux et al, Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma, Nature Cancer (2023). DOI: 10.1038/s43018-023-00649-1

Journal information: Nature Cancer
Citation: Copycat nutrient leaves pancreatic tumors starving, may inform cancer treatment (2023, October 10) retrieved 24 February 2024 from https://medicalxpress.com/news/2023-10-copycat-nutrient-pancreatic-tumors-starving.html
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