Preclinical Study Results Shows Ketogenic Diet May Enhance Pancreatic Cancer Therapy

A common weight-loss diet may enhance the efficacy of chemotherapy for pancreatic cancer, new study results from Ludwig Cancer Research show.

The study results, which are published in Med, show that a ketogenic diet, or high fat, modest protein, and very low carbohydrate intake, synergizes with chemotherapy to triple survival time compared with chemotherapy alone in rigorous mouse models of pancreatic ductal adenocarcinoma (PDAC), according to investigators.

They also described findings from an intricate examination of how ketogenic diets can affect the metabolism of PDAC tumors and identify mechanisms that might account for the therapeutic events. Their findings are being evaluated in a clinical trial (NCT04631445) testing the benefits of a ketogenic diet in patients with PDAC who are receiving chemotherapy.

“There’s been real progress against pancreatic cancer over the past 2 decades,” Joshua Rabinowitz, the director of the Ludwig Cancer Princeton Branch in New Jersey, said in a statement.

“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 6 months to a year, but way too rarely do we see the 3-plus years of extension in survival that people would, at a minimum, hope for,” Rabinowitz said.

Substantial preclinical evidence suggests that fasting, or diets that resemble fasting in their metabolic effects, could enhance therapy for a variety of cancers.

The ketogenic diet mimics fasting by reducing circulating glucose and depressing levels of insulin, a hormone that drives tissues and tumors to consume the sugar. Insulin is an important promoter of cancer growth, especially in pancreatic tumors, while glucose is a critically important fuel for cancer cell proliferation.

In previous studies by Rabinowitz, PDAC tumors were shown to be starved of glucose, which suggested that they could be especially vulnerable to additional glucose deprivation.

In the current study, investigators used mice that were engineered to develop PDAC or implanted with tumors that resembled those seen in individuals with PDAC. The mice were fed either a normal, carbohydrate-rich diet or a ketogenic diet and treated with a standard-of-care combination of chemotherapies, including cisplatin, gemcitabine, and nab-paclitaxel.

Investigators found that the ketogenic diet alone did not affect tumor growth. However, it did triple median survival time when combined with chemotherapy.

Additionally, while the therapeutic benefit did not depend on the immune system, only mice with intact immune systems were among the long-term survivors.

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, including 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,” Rabinowitz said. “Fortuitously, too much of this super-charged fuel may be toxic to cancer.”

The excess of electrons causes the generation of reactive oxygen species (ROS), extremely unstable molecules that are also generated by chemotherapy. ROS kill cancer cells by damaging DNA, membranes, and other components of cells.

Investigators hypothesized that this may enhance the antitumor effects of chemotherapy.

Reference

Ludwig Princeton preclinical study shows ketogenic diet could enhance pancreatic cancer therapy. EurekAlert. News release. February 11, 2022. Accessed February 14, 2022. https://www.eurekalert.org/news-releases/943245