Ketogenic Diet Improves Pancreatic Cancer Therapy in Animal Model

A study investigating the effects of fasting and the ketogenic diet has revealed a new vulnerability of pancreatic tumors to a cancer drug currently in clinical trials. If effective in humans, this could represent a potential Achilles’ heel for one of the deadliest cancer types.

The study was published in Nature.

Potential benefits of fasting/ketogenic diet

Fasting or consuming a ketogenic (high-fat) diet causes the body’s metabolism to switch from using simple sugars like glucose for energy to using ketone bodies produced in the liver from fatty acids. This may lead to health benefits such as decreased inflammation or protection against cancer.

But could diet also play a role in influencing the efficacy of some cancer therapies? For example, pancreatic cancer, where just 13% of patients survive for 5 years after their diagnosis.

While investigating how a protein called eukaryotic translation initiation factor (eIF4E) is involved in this switch in metabolism, researchers from the University of California, San Francisco (UCSF) found that tumors in a mouse model of pancreatic cancer shrank when they received a combination of a ketogenic diet and a drug that targets eIF4E activation.

“We asked how, during different nutrient availability such as fasting or a high-fat diet, do organs such as the liver metabolize specific nutrients to use as energy sources in the body,” Davide Ruggero, a professor in the Department of Cellular and Molecular Pharmacology at UCSF and the senior author of the study, told Technology Networks. “We were particularly interested in fasting, or nutrient deprivation.”

Identifying an Achilles’ heel

The researchers found that, during fasting or on a ketogenic diet, eIF4E in the liver becomes more active, even as the liver paused its other metabolic activity. eIF4E was activated by the presence of free fatty acids, which are released by fat cells early in fasting.

This inspired Ruggero to test the effects of a drug that prevents eIF4E activation: “There was a recent study that showed that pancreatic cancers metabolize ketone bodies as their energy source,” Ruggero said. “If pancreatic cancer uses eIF4E phosphorylation to utilize ketone bodies as their only energy source in a ketogenic diet, then this is a point of vulnerability, because we have a compound that can target eIF4E phosphorylation.”

The drug, eFT508, prevents eIF4E activation and the ketogenic pathway, blocking fat metabolism. It has already been used in human trials, with data suggesting it is well tolerated by cancer patients.

Strikingly, the pancreatic cancer mice on the normal diet were given eFT508 it had little effect and the tumors continued to grow, fueled by other energy sources such as carbohydrates. However, mice on the ketogenic diet who received the drug saw their tumors shrink, cutting off the tumor cells’ only form of sustenance.

“Normal cells don’t need such high amount of eIF4E phosphorylation, but [these] cancer cells are the opposite. That’s the therapeutic window – the cancer cells are addicted,” Ruggero explained. “If you reduce it a little in these addicted cells, they suffer more.”

Moving forward to the clinic

Ruggero and colleagues plan to use this data to conceptualize a trial. “This compound that we used has already been used in the clinic and passed a lot of steps needed to launch a compound in the clinic,” Ruggero said.

“This is in the context of pancreatic cancer, but we hope that new research we are undertaking will increase our knowledge of cancers that we know may respond in a different way to ketogenic diet,” he continued. “We are going to screen many specific diets or nutrient availabilities, such as carbohydrates or vitamins, so how these can be combined with already approved or experimental drugs.”

Reference: Yang H, Zingaro VA, Lincoff J, et al. Remodelling of the translatome controls diet and its impact on tumorigenesis. Nature. 2024:1-9. doi: 10.1038/s41586-024-07781-7

About the interviewee:

Dr. Davide Ruggero is a professor in the Department of Cellular and Molecular Pharmacology at UCSF. He earned his BS in biology and PhD in molecular and cellular biology from the University of Roma La Sapienza, Italy. His current research interests include how impairments in mRNA translation and overall protein synthesis affect human disease and cancer.