21July2018

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Ketogenic diet could save cancer drugs from being ineffective

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 Sonali Thakur
A groundbreaking clinical trial on whether a ketogenic diet could boost the effectiveness of cancer drugs is set to be launched by a team of scientists, including one of Indian origin.

The work, led by scientists in Columbia University Medical Centre in New Work, will investigate whether a high fat, low-carbohydrate diet could improve outcomes for patients with lymphoma and endometrial cancer.

In a study, 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.

Lewis C. Cantley, Senior Author, Ph.D. ’75, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, said, “Any drug that targets PI3K may not be effective unless patients can maintain low blood sugar levels through diet or medication”.

Mr. Cantley said, “We demonstrated that if we keep insulin down with the ketogenic diet, it dramatically improves the effectiveness of these cancer drugs.”

Some of the most common genetic mutations seen in cancerous tumors affect PI3K. The frequency of mutations in the gene has made it an appealing target for cancer drugs, and more than 20 therapies that inhibit the PI3K enzyme have entered into clinical trials.

But so far, the clinical trials’ results have been disappointing. Some patients taking these drugs develop excessively high levels of blood sugar or hyperglycemia.

This is often temporary because the pancreas can usually compensate by producing more insulin. But some patients’ blood sugar levels don’t return to normal and they must stop taking the drugs.

Siddhartha Mukherjee, an oncologist from Columbia University Irving Medical Center in the US, 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”.

“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," he said.

"The ketogenic diet turned out to be the perfect approach. It reduced glycogen stores, so the mice could not release glucose in response to PI3K inhibition," said Benjamin D Hopkins from Weill Cornell Medicine.

"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," he said.

The researchers, however, cautioned that the ketogenic diet alone may not necessarily help control cancer growth and in some cases may even be harmful, like in some cases leukemias.

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

Mr. Cantley, explained, “Reactivating PI3K in the tumor makes the drug relatively ineffective. The rebound elevation in insulin is rescuing the tumor from death.”

Mr. Cantley said, “We have to make sure there is not some unanticipated toxicity”.

In the meantime, Mr. Cantley suggested that investigators test drugs in this class monitor patients’ diets to control blood sugar levels.

“In any clinical trial for a drug that targets the PI3K enzyme, the patient should have their diet managed carefully,” he said.

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