The latest Nature: High-fat, low-carbohydrate diet makes "anticancer drugs" more effective!

In the paper "Suppression of insulin feedback enhances the efficacy of PI3K inhibitors", the team led by Dr. Lewis C. Cantley "Why are the anti-inflammase-activated enzyme PI3K (PI3K mutations  associated with various cancers) resistant? A possible explanation for the fact that the cancer drug  did not achieve the desired effect. At the same time, the study proposes a viable strategy that is expected to increase the anticancer potential of such therapies.

R&D dilemma targeting PI3K

The frequent mutation of PI3K makes this gene an attractive target for anticancer drugs. Currently, more than 20 therapies that inhibit PI3K have entered clinical trials, but so far the results have been disappointing. Some patients taking these drugs have become too high in blood sugar levels or have hyperglycemia. However, this condition is usually temporary because the patient's pancreas can lower blood sugar by producing more insulin, but some patients' blood sugar cannot return to normal levels, so they have to stop taking the medicine.

Dr. Benjamin D. Hopkins, the first author of the paper, said: "In theory, if we turn off the PI3K pathway that promotes cancer cell growth, we should be able to see the patient's clinical response to these drugs, but the results are not as we expected."

Increased insulin levels

So, where is the problem? In this study, Dr. Hopkins et al found that elevated insulin levels reactivated PI3K in mice bearing pancreatic tumors treated with the PI3K inhibitor Buparlisib.

The authors say it is the rise in insulin that has saved tumors from death. Reactivation of PI3K in tumors makes PI3K inhibitors relatively ineffective.

After obtaining the above findings, scientists hope to find a way to help control blood sugar and insulin levels. In the next experiment, in addition to PI3K inhibitors, they were also treated with the diabetes drug metformin or SGLT2 inhibitor or ketogenic diet.

The results show that 1) metformin, which increases insulin sensitivity, does not have much effect on glucose or insulin peaks or cell signals that promote tumor growth; 2) SGLT2 inhibitors that prevent glucose reabsorption in the kidney reduce glucose and insulin Peak and tumor growth signals; 3) The ketogenic diet, which has been used clinically for about 40 years to control insulin levels, has done the best in preventing glucose and insulin surges and inhibiting tumor growth signals.

“The ketogenic diet proved to be the perfect method. It reduced the storage of glycogen, so mice could not release glucose in response to PI3K inhibitors. This suggests that PI3K inhibition can be prevented if glucose agitation and subsequent insulin feedback are prevented. Agents are more effective at controlling cancer growth," Dr. Hopkins explained.

However, Dr. Hopkins warns that the ketogenic diet alone does not necessarily help control cancer growth, and in some cases it may even be harmful. In the study, when scientists investigated the effects of the ketogenic diet in a variety of cancer mice in the absence of PI3K inhibitors, they found that the ketogenic diet had little effect on the tumor and caused some leukemias to develop more fast.

Dr. Lewis Cantley. Photo credit Stephanie Diani

Dr. Cantley said that any drug that targets PI3K may be ineffective unless the patient is able to maintain low blood sugar levels through diet or medication. Next, they hope to investigate whether it is safe to combine FDA-approved intravenous PI3K inhibitors with the ketogenic diet (specially prepared  by nutritionists) for patients with breast cancer, endometrial cancer, leukemia or lymphoma, and can improve Treatment outcome.

“This research represents a truly innovative cancer therapy. For decades, we have been trying to change human metabolism and make cancer cells more sensitive to chemotherapy or targeted drugs. We will try this treatment in humans. I am very excited," concluded Dr. Siddhartha Mukherjee, co-author  of the paper.