A very low carbohydrate, high-fat diet called the ketogenic diet might improve the effectiveness of an emerging class of cancer drugs, according to a study at Weill Cornell Medicine, Columbia University Irving Medical Center and NewYork-Presbyterian.

In a study published in Nature on July 4, scientists provide a possible explanation for why the drugs, which target the insulin-activated enzyme phosphatidylinositol-3 kinase (PI3K) whose mutations have been implicated in many cancers, haven't performed as well as hoped. And they identify a strategy that might boost the therapies' tumor-killing potential.

The ketogenic diet boosts targeted cancer therapy

"Any drug that targets PI3K may not be effective unless patients can maintain low blood sugar levels through diet or medication," said senior author Dr. Lewis C. Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

"We demonstrated that if we keep insulin down with the ketogenic diet, it dramatically improves the effectiveness of these cancer drugs," said Dr. Lewis C. Cantley.

"If we turn off the PI3K pathway, which promotes the growth of cancer cells, we should see a clinical response to these drugs, and we just do not," said lead author Dr. Benjamin D. Hopkins, a postdoctoral associate at Weill Cornell Medicine.

In the study, Dr. Hopkins and his coauthors demonstrated that rising insulin levels reactivate PI3K in mice with pancreatic tumors treated with a PI3K-inhibitor called Buparlisib.

"Reactivating PI3K in the tumor makes the drug relatively ineffective," said Dr. Cantley, a professor of cancer biology in medicine at Weill Cornell Medicine. "The rebound elevation in insulin is rescuing the tumor from death."

Metformin, which increases insulin sensitivity, did not have much effect on the glucose or insulin spikes, or on cellular signals that promote tumor growth. The SGLT2 inhibitors, which prevent the re-absorption of glucose in kidneys so that it is removed in urine, reduced the glucose and insulin spikes in response to PI3K treatment and reduced tumor growth signals.

Importantly, the ketogenic diet, which has been used in the clinic for about four decades to control insulin levels, did the best job at preventing glucose and insulin spikes and tamping down tumor growth signals.

"The ketogenic diet turned out to be the perfect approach," Dr. Hopkins said. "It reduced glycogen stores so that the mice could not release glucose in response to PI3K inhibition."

"This suggests that if you can block spikes in glucose and the subsequent insulin feedback, you can make the drugs much more effective at controlling cancer growth," Dr. Hopkins said.

"This study represents a truly innovative approach to cancer. For decades, we have been trying to alter human metabolism to make cancer cells more sensitive to chemotherapy or targeted drugs," said co-senior author Dr. Siddhartha Mukherjee, associate professor of medicine at the Columbia University Vagelos College of Physicians.

"The fact that this drug itself was enabling a kind of resistance at least in animal models comes as a total surprise. We are excited to try this approach in humans," said Mukherjee.