Keto diet could make cancer therapy more effective

A new study in mice finds that the ketogenic, or keto, diet helps to eliminate the side effects of a new generation of cancer drugs.

In recent years, scientists have been testing a new class of cancer drugs.

They target a specific molecular pathway that has been shown to be faulty in many types of cancer.

Specifically, these drugs target a cell signaling pathway called phosphatidylinositol-3 kinase (PI3K), which is activated by insulin.

Previous studies have shown that mutations in this kinase, or enzyme, are present in most tumors.

So, in an attempt to inhibit this pathway, over 50 drugs have been developed, with several clinical trials testing their efficacy.

Thus far, however, the results of these trials have been disappointing; for the most part, the drugs' efficacy is hit-or-miss, or their toxicity is too high.

Taking these drugs often leads to hyperglycemia, or abnormally high levels of blood sugar. This occurs because inhibiting the pathway causes the insulin to drop, which increases blood sugar levels.

When the pancreas is unable to make up for the loss by producing more insulin, patients have to stop taking the drugs. Now, however, researchers led by Benjamin D. Hopkins, a postdoctoral associate at Weill Cornell Medicine in New York City, NY, may have found a way around this problem.

The "trendy" ketogenic diet — a diet high in fats but very low in carbs — may be the best way to boost the efficacy of these new-generation therapies and avoid their side effects.

The researchers published their findings in the journal Nature.

Insulin affects the efficacy of cancer drugs

Hopkins and colleagues examined the effect of a PI3K-inhibiting drug called buparlisib in a mouse model of pancreatic cancer.

The model revealed that increasing insulin levels reactivates the PI3K pathway, defeating the purpose of the cancer drug.

"Reactivating PI3K in the tumor makes the drug relatively ineffective," explains corresponding study author Lewis C. Cantley, a professor of cancer biology in medicine at Weill Cornell Medicine.

"The rebound elevation in insulin is rescuing the tumor from death," he goes on. So, to counter this effect, the researchers decided to try a few different blood sugar- and insulin-controlling drugs. They treated one group of mice with diabetes drugs, and another with a ketogenic diet.

'A truly innovative approach to cancer'

Of all the treatments tested, the keto diet performed best at both keeping blood sugar and insulin in check and simultaneously inhibiting tumor growth signals.

"The ketogenic diet turned out to be the perfect approach," says Hopkins. "It reduced glycogen stores, so the mice couldn't release glucose in response to PI3K inhibition."

"This suggests," he continues, "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."

Co-senior author Dr. Siddhartha Mukherjee — an associate professor of medicine at the Columbia University Vagelos College of Physicians and Surgeons in New York City, NY — also weighs in on the findings.

"This study represents a truly innovative approach to cancer. For decades, we've been trying to alter human metabolism to make cancer cells more sensitive to chemotherapy or targeted drugs."

Dr. Siddhartha Mukherjee

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

However, the authors caution that this is a combination approach, and that the keto diet on its own does not help to inhibit cancer but may even have the opposite effect.

Some mice fed a keto diet without also taking PIK3 inhibitors had faster-growing leukemias, report the researchers.

In the future, the scientists wish to take the combination therapy to human clinical trials for treating breast cancer, endometrial cancer, and blood cancer.

"We have to make sure there is not some unanticipated toxicity," Prof. Cantley says. "In any clinical trial for a drug that targets the PI3K enzyme, the patient should have their diet managed carefully."