Scientists have found a method to eliminate pancreatic cancer in mice by placing them on a high-fat, ketogenic diet while administering cancer treatment.
A study focusing on fasting and the ketogenic diet has unveiled a new weakness in pancreatic tumors that can be targeted with an existing cancer medication.
Researchers at UC San Francisco have successfully eliminated pancreatic cancer in mice by placing them on a ketogenic diet along with cancer treatment.
The cancer therapy works by blocking fat metabolism, which is the sole energy source for pancreatic tumors as long as the mice are on the ketogenic diet, leading to a halt in tumor growth.
This discovery, published on August 14 in Nature, came about while the team was investigating how the body survives on fat during fasting periods.
Davide Ruggero, PhD, who leads the study and holds the Goldberg-Benioff Endowed Professorship, stated, “Our research led us directly to understanding one of the most lethal cancers, pancreatic cancer.”
The team first identified how a protein called eukaryotic translation initiation factor (eIF4E) alters the metabolism to utilize fat during fasting. This fat-switching mechanism is also triggered by eIF4E when an animal follows a ketogenic diet.
They discovered that a new cancer drug, eFT508, currently being tested in clinical trials, inhibits eIF4E and the ketogenic pathway, effectively preventing the metabolism of fat. When this drug was combined with a ketogenic diet in a mouse model of pancreatic cancer, the cancer cells were starved.
“Our findings highlight a potential point of weakness that can be targeted with a clinical inhibitor that is already deemed safe for humans,” Ruggero commented. “We now possess strong evidence showing how diet can be utilized alongside existing cancer treatments to eradicate cancer effectively.”
Utilizing different energy sources in cellular processes
Humans can survive for weeks without food because the body utilizes stored fat for energy.
During fasting, the liver transforms fats into ketone bodies to replace glucose, the body’s typical energy source. Ruggero’s team discovered that eIF4E in the liver becomes more active while other metabolic activities are slowed down, indicating its role in producing ketone bodies, a process known as ketogenesis.
Haojun Yang, PhD, a post-doctoral researcher in Ruggero’s lab and the lead author of the study, noted, “Fasting has been integral to numerous cultural and religious practices for centuries, often believed to enhance health. Our discovery that fasting changes gene expression provides a possible biological explanation for these advantages.”
By examining how metabolic pathways shifted during fasting, the researchers found that eIF4E was activated by free fatty acids, which are released by fat cells at the onset of fasting, supplying the body with something to utilize.
“The metabolite that the body uses for energy simultaneously acts as a signaling molecule during fasting,” Ruggero observed. “To a biochemist, it’s fascinating to see a metabolite function as a signal.”
Similar changes in the liver—ketone body production through fat burning and increased eIF4E activity—were also observed in laboratory animals given a ketogenic diet rich in fats.
This prompted a significant realization.
“Once we understood how the pathway operates, we recognized the opportunity to intervene,” Ruggero remarked.
Targeting the weak spot of pancreatic cancer
The researchers initially treated pancreatic cancer with eFT508, the drug designed to inhibit eIF4E, aiming to curb tumor growth. However, the pancreatic tumors continued to grow as they found alternative fuel sources like glucose and carbohydrates.
Realizing that pancreatic cancer can thrive on fat and that eIF4E is more active during fat metabolism, the scientists first placed the mice on a ketogenic diet, forcing the tumors to rely solely on fats, and then introduced the cancer drug. In this scenario, the drug deprived the cancer cells of their only energy source—resulting in shrinking tumors.
Ruggero, along with Kevan Shokat, PhD, who is also a UCSF professor of cellular and molecular pharmacology, developed eFT508 in the 2010s, which showed potential during clinical trials. However, there’s now a more powerful way to implement it.
“The field has struggled to establish a clear relationship between diet and cancer treatments,” Ruggero explained. “To successfully connect these areas, a thorough understanding of the underlying mechanism is essential.”
Diverse diet-drug pairings will be necessary to treat various types of cancer.
“We anticipate that most cancers will show unique vulnerabilities,” Ruggero stated. “This lays the groundwork for a novel approach to cancer treatment combining diet with personalized therapies.”
