Keto diet plus experimental drug may shrink pancreatic tumors
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Key takeaways:
- An experimental MNK inhibitor in combination with a ketogenic diet shrunk pancreatic tumors in mice.
- Dietary intervention could become a key component of cancer therapy.
The combination of a ketogenic diet and an experimental MNK inhibitor may be able to shrink pancreatic cancer tumors, according to preliminary study findings.
In mouse models, eFT508 (eFFECTOR Therapeutics) — also known as tomivosertib — inhibited phosphorylation of the major cap-binding protein and translation factor eIF4E, which Ruggero and colleagues found to be critical for the production of ketone bodies.
The cancer needed to survive upon ketogenic diet and eFT508 eliminated the disease’s energy sources (ketone bodies), which caused tumors to shrink.
“You’re changing the food that you give to the cancer,” Davide Ruggero, PhD, professor of urology, Helen Diller family endowed chair in basic cancer research and principal investigator at Ruggero Lab at University of California, San Francisco, told Healio. “If you know which they like [and] which they don't like — that can be very powerful.”
‘Master regulator’
Ruggero and colleagues did not begin their research investigating pancreatic cancer.
Instead, they evaluated how the liver produces specific proteins when a body fasts, whether during sleep or purposeful consumption.
Fasting caused fatty acids to go to the liver to be turned into useful energy, and that signaled eukaryotic translation initiation factor 4E (eIF4E) phosphorylation.
eIF4E — a protein coding gene —is the “master regulator building the right proteins in the liver that they needed to burn fat, to produce ketone bodies that are an alternative source of energy,” Ruggero said. “These ketone bodies circulate in the blood and go to the heart and brain muscle. They also provide the energy.”
The drug eFT508, a highly selective oral inhibitor of MNK1/2 kinases that mediate tumor immune evasion and are activated downstream of MEK and MAPK signaling, has been tested in clinical trials to treat a variety of cancer types.
Ruggero and colleagues developed the drug in the 2010s and knew it blocked eIF4E phosphorylation. And because pancreatic cancer tumors “love” ketone bodies as an energy source, researchers thought this could be a vulnerability.
‘Efficacious’ approach
Ruggero and colleagues tested eFT508 in mice with pancreatic cancer, but the tumors continued growing because they survived on carbohydrates and other nutrients, Ruggero said.
Investigators then put mice on ketogenic diets and tried again.
“Depending on the preclinical trial that we were doing, [tumors decreased] from 30% to even 70%,” Ruggero said. “We were using very aggressive pancreatic cancers. The tumors were growing very fast. This combination was very efficacious. We were very, very excited.”
Body weight, food intake, blood glucose, glycerol, free fatty acid and insulin levels did not change in the mice.
“When you give eFT508 and a ketogenic diet, the normal cells — even if you reduce their ability to use 30% of fat — are still fine because the amount of energy that they require is not the same as the amount of energy that the cancer cells require,” Ruggero said. “That is the one of the most important aspects of the therapeutic window.”
Dietary intervention will be ‘big’
Ruggero said clinicians have reached out to him regarding a potential future trial, but nothing has been established yet.
“If there is the possibility, that would be great,” he said.
Regardless of if or when this concept advances to trials, dietary intervention will be a “big field” in cancer therapy, Ruggero said.
As Healio previously reported, data from another preclinical study showed immunotherapy combined with a ketogenic diet reduced prostate cancer tumors and improved survival.
“We are doing a lot of experiments to understand exactly how many other cancer types can be sensitive or respond as pancreatic cancer did to this combination therapy,” Ruggero said. “We are trying to broaden our view of diet and metabolites in the context of which of them, and how many of them, can really change the life of cancer.
“There are many other diets or different conditions that the cancer can respond to in different ways,” he added. “I think the overall concept of changing nutrients in the body and how this affects the life of a cancer, or how changing nutrients in the body can affect the therapy response, is big.”
For more information:
Davide Ruggero, PhD, can be reached at davide.ruggero@ucsf.edu.
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