How the ketogenic diet could improve efficacy of a new experimental cancer drug
A fascinating study by a team of researchers from Weill Cornell Medicine, Columbia University Irving Medical Center and NewYork-Presbyterian has found that the ketogenic diet may improve the efficacy of a new class of cancer drug that has been inexplicably showing disappointing results in early human clinical trials.
The research began by attempting to understand why a promising new type of cancer drug designed to target an enzyme called phosphatidylinositol-3 kinase (PI3K) was proving relatively ineffective in early human clinical trials. Many common cancers display mutations in the pathway that regulates PI3K and the hope was that by inhibiting the pathway the treatment would kill tumors.
"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 don't," explains Benjamin D. Hopkins, lead author on the new study.
The first stages of the research in mouse models revealed that animals treated with a PI3K-inhibitor were found to have their PI3K pathways reactivated in the presence of rising insulin levels. Effectively, when an animal's glucose levels rose, the body produced insulin that essentially worked to counteract any PI3K inhibition produced by the drug.
The researchers then set out to test a variety of methods that modulate insulin and blood sugar levels to see if they improved responsiveness to PI3K treatments. Two diabetes drugs were tested. One, called metaformin didn't prove effective in reducing tumor growth, while another, known as a sodium-glucose co-transporter 2 inhibitor, did seem to reduce tumor growth signals.
The study also tested whether placing the animals on a ketogenic diet was effective in regulating insulin levels and improving responses to the PI3K treatment. Unexpectedly, the ketogenic diet, used for some years in clinical contexts to control insulin levels, was the most effective technique tested.
"The ketogenic diet turned out to be the perfect approach," explains Hopkins. "It reduced glycogen stores, so the mice couldn't 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."
In recent years, the growing popularity of the ketogenic diet has caused some to laud it as a cure-all for many diseases. While there are some advocates that claim a ketogenic diet on its own can cure cancer, there is absolutely no convincing evidence to support this. In fact, Hopkins and his team caution that a ketogenic diet may actually be harmful when administered without any adjunctive medical treatment.
In the course of this research the ketogenic diet was administered to mice models for several cancers, and in most cancers it had little to no effect on the tumors when delivered in isolation. At worst, in a test for leukemia, the ketogenic diet actually made the cancer grow faster when administered without a PI3K-inhibitor. Other studies targeting certain types of skin cancers have also shown that a ketogenic diet can enhance tumor growth. But, as an adjunct to other cancer therapies there is a compelling, and growing, body of evidence suggesting that the diet can potentially be helpful. A number of clinical trials are currently underway testing the efficacy of a ketogenic diet alongside other therapies.
This particular study has immediately applicable benefits to several currently ongoing clinical trials. Although this research was only demonstrated in mouse models, the researchers suggest that the PI3K human trials currently underway should commence monitoring patients' blood sugar levels.
"In any clinical trial for a drug that targets the PI3K enzyme, the patient should have their diet managed carefully," says Lewis Cantley, senior author on the new study.
A human clinical trial into the efficacy of PI3K-inhibitors administered in conjunction with a ketogenic diet is currently awaiting ethical approval so it may be some time before we have a clear indication of how beneficial the diet actually is in this context.
The new research has been published in the journal Nature.
Source: Weill Cornell Medicine