Scientists at the University of California San Francisco (UCSF) have discovered a way to inhibit pancreatic cancer in mice by putting the animals on a high fat, or ketogenic diet, and giving them a cancer therapy called tomivosertib (eFT508). The team made the discovery while they were trying to figure out how the body manages to subsist on fat while fasting.
In their newly reported study the investigators found that the treatment blocked fat metabolism—which represented the cancer’s only source of fuel for as long as the mice remained on the ketogenic diet—and the animals’ pancreatic tumors stopped growing.
“Our findings led us straight to the biology of one of the deadliest cancers, pancreatic cancer,” said Davide Ruggero, PhD, Goldberg-Benioff Endowed Professor and American Cancer Society Research Professor in the Departments of Urology and Cellular Molecular Pharmacology at UCSF. “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.”
Ruggero is senior author of the team’s published report in Nature, titled “Remodelling of the translatome controls diet and its impact on tumorigenesis,” in which they concluded “… our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer.”
Humans can survive for weeks without food, in part because the body burns stored fat. During fasting the liver converts fats into ketone bodies to use in place of glucose, the body’s normal source of energy. “For thousands of years, beginning with Greek philosophers Hippocrates and Plato, fasting has been recommended as a health benefit,” the authors wrote. “Fasting establishes these health benefits through metabolic rewiring, by switching the body’s source of energy from glucose to ketone bodies.”
And while ketogenesis, induced by fasting, low-carbohydrate high-fat diet or exercise, has been shown to activate a variety of cellular signalling pathway, the team continued, “Despite decades of work, how fasting signals elicit changes in gene expression at the level of the proteome to establish metabolic programmes that underlie the production of ketone bodies remains inadequately characterized.”
By tracking how different metabolic pathways changed during fasting, the scientists discovered that a protein called eIF4E was activated by the presence of free fatty acids, which are released by fat cells early in fasting, so the body has something to consume. “We discover that phosphorylation of eukaryotic translation initiation factor 4E (P-eIF4E) is induced during fasting,” the team wrote. They found that eIF4E in the liver became more active, even as the liver paused its other metabolic activity, suggesting that this factor was involved in making ketone bodies, a process called ketogenesis.
“The metabolite that the body uses to make energy is also being used as a signal molecule during fasting,” Ruggero added. “To a biochemist, seeing a metabolite act like a signal was the coolest thing.” These same changes in the liver—ketone body production from burning fat, along with a rise in eIF4E activity—also occurred when laboratory animals were given a ketogenic diet consisting mostly of fat.
“We discovered that during fasting or with a ketogenic diet, P-eIF4E becomes a selective translation factor critical for the translation of specific messenger RNA (mRNA) networks in the liver that are critically required for ketogenesis,” the team further explained. The results of their analyses also indicated that long chain fatty acids, during fasting or with a ketogenic diet, can act as signalling molecules that activate the nutrient sensor, AMP-activated protein kinase (AMPK). This in turn activates the kinase that phosphorylates eIF4E, MAP kinase-interacting protein kinase (MNK). “Once we could see how the pathway works, we saw the opportunity to intervene,” Ruggero said.
Certain cancers, such as pancreatic tumors, can use ketone bodies as an alternative energy source to sustain cancer fitness, the authors noted. They discovered that the new cancer drug eFT508, which is currently in clinical trials, effectively blocks eIF4E and the ketogenic pathway, preventing the body from metabolizing fat.
“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 first treated pancreatic cancer with eFT508, intending to block tumor growth. Yet, the pancreatic tumors continued to grow, sustained by other sources of fuel like glucose and carbohydrates.
Knowing that pancreatic cancer can thrive on fat, and that eIF4E is more active during fat burning, the scientists then placed the pancreatic cancer mouse models on a ketogenic diet, forcing the tumors to consume fats alone, and treated the animals using the cancer drug. “… we proposed that pancreatic tumour growth, under a ketogenic diet, might also rely on P-eIF4E, which can be blocked by a clinical inhibitor of MNK (eFT508; also known as tomivosertib),” they commented. In this context, the drug cut off the cancer cells’ only sustenance—and the tumors shrank.
Ruggero, along with Kevan Shokat, PhD, UCSF professor of cellular and molecular pharmacology, developed eFT508 in the 2010s, and it showed some promise in clinical trials. But now, there’s a much more powerful way to use it. “The field has struggled to firmly link diet with cancer and cancer treatments,” Ruggero said. “But to really connect these things productively, you need to know the mechanism.” The authors concluded, “The strong repression of tumour growth from the combination of targeting P-eIF4E with a clinical inhibitor and a ketogenic diet revealed a new therapeutic approach for pancreatic cancer treatment in the future. It will be interesting to determine in future studies whether this translational control of ketogenesis is also present in other tissues and tumour types.”
Different diet-drug combinations will be needed to treat more forms of cancer, the researchers suggested. “We expect most cancers to have other vulnerabilities,” Ruggero said. “This is the foundation for a new way to treat cancer with diet and personalized therapies.”
