A preclinical study has demonstrated that a common weight-loss diet could enhance the efficacy of chemotherapy for pancreatic cancer. Published in the journal Med, the study shows that a ketogenic diet—or high fat, modest protein and very low carbohydrate intake—synergizes with chemotherapy to triple survival time compared to chemotherapy alone in rigorous mouse models of pancreatic ductal adenocarcinoma (PDAC). 

The researchers were led by Joshua Rabinowitz, director of the Ludwig Institute for Cancer Research Princeton Branch and professor of chemistry and the Lewis-Sigler Institute for Integrative Genomics at Princeton University. The Ludwig Princeton Branch, established in 2021, is wholly focused on the study of metabolism in the prevention and treatment of cancer.

This Rabinowitz-led investigation extends to an intricate examination of how ketogenic diets affect the metabolism of PDAC tumors, and identifies mechanisms that might account for the therapeutic effect. Their findings are now being evaluated in a clinical trial (NCT04631445) testing the benefits of a ketogenic diet in PDAC patients receiving chemotherapy.

Speaking with the Ludwig Institute for Cancer Research, Rabinowitz said, “There’s been real progress against pancreatic cancer over the past two decades. The problem is that, while a number of patients now see their tumors stabilize or shrink, the benefits of chemotherapy are very short-lived. It often extends patients’ lives six months to a year, but way too rarely do we see the three-plus years of extension in survival that people would, at a minimum, hope for.”

Over many years and with support from Stand Up to Cancer, Rabinowitz and colleagues have conducted multiple experiments on mice, finding that the ketogenic diet alone did not affect tumor growth, but it did triple median survival time when combined with chemotherapy.

Rabinowitz and his team also conducted studies to explore the effects of a standard combination of chemotherapies on tumor metabolism. “We know that glucose is a major cancer fuel, and insulin is a cancer-promoting hormone, and that the ketogenic diet in one stroke decreases both,” Rabinowitz explained. “We found in this study that the diet decreases levels of glucose more profoundly in the tumor than in healthy tissues and that it dramatically suppresses levels of insulin.”

By depriving the body of sugar, the ketogenic diet forces the body to break down fats to generate molecules known as ketone bodies that can be burned by cells to generate energy. Chief among these is 3-hydroxybutyrate.

“One thing we noticed is that 3-hydroxybutyrate acts like a supercharged fuel that dumps electrons into cells, and tumor cells are wired for other reasons to be extra-good at taking up this fuel,” said Rabinowitz. “Fortuitously, too much of this super-charged fuel may be toxic to cancer.”

“I think that the most exciting thing here is that we can take chemotherapy regimens that we know to be active, that offer patients the best chance in the clinic right now and, at least in mice, make them work substantially better by pairing them with a ketogenic diet,” said Rabinowitz. “We hope that we’ll see the same types of benefits in patients.”

This work was supported by Ludwig Cancer Research, Stand Up to Cancer, the U.S. National Institutes of Health, the New Jersey Commission on Cancer Research, American Chemical Society, Rutgers Busch Biomedical Grant, the New Jersey Health Foundation, March of Dimes, the Lustgarten Foundation, the Don and Lorraine Freeberg Foundation and the David C. Copley Foundation.

Rabinowitz is also Director of the Metabolomics Shared Resource at Rutgers Cancer Institute.

Adapted with permission from the Ludwig Institute for Cancer Research.