Scientists at the University of California, San Francisco, have discovered a way to starve pancreatic cancer cells, causing them to die. The method was discovered by following a high-fat or ketogenic diet, and preventing the cancer cells from using the fats in this diet as a source of energy by giving a treatment that does this job.
Cutting off energy sources to cancer cells
A new study has uncovered a new vulnerability in pancreatic tumors to an existing cancer drug. The treatment blocks fat metabolism, the cancer’s only source of energy while the mice are on a ketogenic diet, stopping tumor growth. The team discovered this while trying to figure out how the body continues to live on fat during fasting. The findings were published Aug. 14 in the journal Nature.
“Our findings lead directly to an understanding of the life cycle of one of the most deadly cancers, pancreatic cancer,” said Dr. David Ruggiero, an American Cancer Society investigator in the departments of urology and cellular and molecular pharmacology at UCSF and the study’s lead author.
Ruggiero’s team first discovered how a protein, known as eukaryotic translation initiation factor 4E (eIF4E), changes the body’s metabolism to shift to fat consumption during fasting, and the same shift also occurs thanks to eIF4E when the animal is on a ketogenic diet.
The team found that a new cancer drug called eFT508, which is currently in clinical trials, blocks a translation initiation factor in eukaryotic cells and the ketogenic pathway, preventing the body from using fat as an energy source. When the scientists combined the drug with a ketogenic diet in an animal model of pancreatic cancer, the cancer cells starved.
“Our results open up a weakness that we can address with an inhibitor drug that we already know is safe to use in humans,” Ruggiero said. “We now have strong evidence of how diet can be used alongside existing treatments to precisely eliminate cancer.”
Burning different fuels in the cell’s “engine”
Humans can survive for weeks without food, in part because the body burns stored fat. During fasting, the liver converts fat into ketone bodies to be used instead of glucose, the body’s natural source of energy. Ruggiero’s team found that a translation initiation factor in eukaryotic cells in the liver became more active, even when the liver stopped its other metabolic activities, suggesting that this factor was involved in the process of ketone body production.
“Fasting has been part of cultural and religious practices for centuries and is often thought to promote health,” said Haojun Yang, Ph.D., a postdoctoral researcher in Ruggiero’s lab and the study’s first author. “Our discovery that fasting reshapes gene expression provides a possible biological explanation for these benefits.”
By tracking how different metabolic pathways change during fasting, the scientists discovered that a translation initiation factor in eukaryotic cells is activated in the presence of free fatty acids, which the body releases early in the fast for consumption.
“The metabolite that the body uses to generate energy is also used as a signaling molecule during fasting, and for a biochemist, seeing a metabolite acting as a signal was something amazing,” Ruggiero said, according to EurekAlert.
The same changes in the liver—production of ketone bodies from fat burning, along with increased activity of a translation initiation factor in eukaryotic cells—also occurred when lab animals were fed a ketogenic diet consisting mostly of fat. That’s when the researchers had a lightbulb moment. “Once we could see how the pathway worked, we saw an opportunity to intervene,” Ruggiero says.
Exploiting the Achilles’ heel of pancreatic cancer
Scientists first treated pancreatic cancer with the cancer drug eFT508, which blocks a factor in eukaryotic cells, with the goal of preventing tumor growth. However, pancreatic tumors continued to grow, feeding on other sources of fuel such as glucose and carbohydrates.
Knowing that pancreatic cancer can thrive on fat, and that the translation initiation factor in eukaryotic cells is most active when they burn fat, the scientists first put the animals on a ketogenic diet, forcing the tumors to consume only fat, and then gave them the cancer drug. In this context, the drug cut off the cancer cells’ only source of nutrition, and the tumors shrank.
Ruggiero, along with Dr. Kevan Shokat, a professor of cellular and molecular pharmacology at the University of California San Francisco, developed eFT508 in 2010, and it showed some promise in clinical trials, but now there’s a much more powerful way to use it.
“In this field, we have difficulty making clear connections between diet, cancer and cancer treatments, but in order to make these connections productively, we need to know the mechanism,” Ruggiero said, according to EurekAlert.
A combination of diet and medication will be needed to treat more types of cancer.
Ruggiero expected that most cancers would have other weaknesses, adding, “This is the basis for a new way to treat cancer through diet and personalized therapies.”