Ketogenic Diet Enhances Pancreatic Cancer Therapy

A novel way for pancreatic tumors to be exposed to an existing cancer medication is revealed by a study on fasting and the ketogenic diet.

Researchers at UC San Francisco have found that treating mice with cancer therapy plus a high-fat, or ketogenic, diet can completely eradicate pancreatic cancer in mice.

As long as the mice are on the ketogenic diet, the cancer therapy prevents fat metabolism, which is the only source of fuel for the cancer, and the tumors cease growing.

The team was attempting to determine how the body sustains itself on fat while fasting when they made the discovery, which is published in Nature on August 14.

Senior author of the paper Davide Ruggero, PhD, Goldberg-Benioff Endowed Professor and American Cancer Society Research Professor in the Departments of Urology and Cellular Molecular Pharmacology at UCSF, said, “Our findings led us straight to the biology of one of the deadliest cancers, pancreatic cancer.”

First, Ruggero’s group discovered how the body shifts its metabolism during fasting to burn fat by means of a protein called eukaryotic translation initiation factor (eIF4E). Thanks to eIF4E, the same switch happens when an animal follows a ketogenic diet.

They discovered that eIF4E and the ketogenic pathway are blocked by a novel cancer treatment called eFT508, which is presently undergoing clinical trials and keeps the body from metabolizing fat. The medication starved the cancer cells in an animal model of pancreatic cancer when the researchers paired it with a ketogenic diet.

“Our findings open a point of vulnerability that we can treat with a clinical inhibitor that we already know is safe in humans. We now have firm evidence of one way in which diet might be used alongside pre-existing cancer therapies to precisely eliminate a cancer.”- Davide Ruggero, PhD, Goldberg-Benioff Endowed Professor and American Cancer Society Research Professor in the Departments of Urology and Cellular Molecular Pharmacology at UCSF

burning various fuels in the cell’s engine
Because the body burns stored fat, humans can go for weeks without eating.

The liver uses ketone bodies produced during fasting to replace the body’s usual energy source, glucose. Ruggero’s group discovered that even when the liver stopped its other metabolic processes, eIF4E in the liver grew more active, indicating that this factor was engaged in the process known as ketogenesis, which produces ketone bodies.

“Fasting has been part of various cultural and religious practices for centuries, often believed to promote health,” said Haojun Yang, PhD, post-doctoral researcher in Ruggero’s lab and first author of the study. “Our finding that fasting remodels gene expression provides a potential biological explanation for these benefits.”

The scientists saw that eIF4E was triggered by the presence of free fatty acids, which are released by fat cells early in fasting to provide the body with something to eat, by monitoring how several metabolic pathways changed during fasting.

“The metabolite that the body uses to make energy is also being used as a signal molecule during fasting,” Ruggero said. “To a biochemist, seeing a metabolite act like a signal was the coolest thing.”

The same alterations in the liver that resulted from burning fat to produce ketone bodies and an increase in eIF4E activity also happened when lab animals were fed a ketogenic diet high in fat.

The bulb went out at that point.

“Once we could see how the pathway works, we saw the opportunity to intervene,” Ruggero stated.

The weakness in pancreatic cancer
The researchers initially used eFT508, a cancer medication that inhibits eIF4E, to treat pancreatic cancer in an effort to stop tumor growth. Nevertheless, the pancreatic tumors persisted in growing because they had access to additional fuel sources like glucose and carbs.

The scientists first put the mice on a ketogenic diet, forcing the tumors to consume fats alone, and then started them on the cancer medication because they knew that pancreatic cancer can grow on fat and that eIF4E is more active during fat burning. Here, the medication eliminated the sole source of nutrition for the cancer cells, causing the tumors to shrink.

In the 2010s, Ruggero and UCSF professor of cellular and molecular pharmacology Kevan Shokat, PhD, created eFT508, which had some promise in clinical trials. However, there’s a far more potent application for it now.

“The field has struggled to firmly link diet with cancer and cancer treatments,” Ruggero stated. “But to really connect these things productively, you need to know the mechanism.”

Treatments for more types of cancer will require different diet-drug combinations.

“We expect most cancers to have other vulnerabilities,” Ruggero stated. “This is the foundation for a new way to treat cancer with diet and personalized therapies.”

For more information: Remodelling of the translatome controls diet and its impact on tumorigenesis, Nature, http://doi.org/10.1038/s41586-024-07781-7