On July 4th, Nature published an article named Suppression of insulin feedback enhances the efficacy of PI3K inhibitors In the paper, a team led by Dr. Lewis C. Cantley offered a possible explanation for why anticancer drugs targeting the insulin activator PI3K (a mutation in PI3K associated with multiple cancers) did not achieve the desired effect. At the same time, a feasible strategy is proposed to improve the anticancer potential of these therapies.
Difficulties of targeting PI3K development
The frequent mutation of PI3K makes the gene an attractive target for anticancer drugs. More than 20
PI3K inhibitory therapies have been tested in clinical trials, but so far the results have been disappointing. Some patients who take these drugs become hyperglycemic or suffer from hyperglycemia. However, this is usually temporary, because the pancreas of the patient can produce more insulin to lower blood sugar, but some patients can not return to normal blood sugar levels, so have to stop taking drugs.
Dr Benjamin D. Hopkins, the lead author of the paper, said: "Theoretically, if we shut down the PI3K pathway that promotes cancer cell growth, we should be able to see the clinical response of patients to these drugs, but the results did not meet our expectations."
Increased insulin level cause the trouble
So where is the problem? In this study, Dr Hopkins and others found that elevated insulin levels reactivated PI3K in mice with pancreatic tumors treated with
PI3K inhibitor Buparlisib.
The authors say that it is insulin rebound that raises the cancer from death. Reactivation of PI3K in the tumor makes PI3K inhibitors relatively ineffective.
Ketogenic diet perform "best"
With these findings, scientists hope to find a way to help control blood sugar and insulin levels. In the following experiments, in addition to PI3K inhibitors, they also added diabetic drugs metformin or SGLT2 inhibitors or ketogenic diets to treat mice.
The results showed that 1) metformin, which increased insulin sensitivity, had no significant effect on glucose or insulin peak or tumor growth signal; 2) SGLT2 inhibitors, which inhibited glucose reabsorption in the kidneys, reduced glucose and insulin peak and tumor growth signal; 3) were used to control tumor growth. Insulin levels, ketogenic diets that have been used clinically for about 40 years, are best at preventing glucose and insulin surges and suppressing tumor growth signals.
The ketone diet proved to be the perfect way. It reduces glycogen storage, so mice can not release glucose to respond to PI3K inhibitors. This suggests that PI3K inhibitors can be more effective in controlling cancer growth if they prevent glucose surges and subsequent insulin feedback. Dr. Hopkins explained.
However, Dr. Hopkins warns that ketogenic diets alone may not necessarily help control cancer growth, and in some cases it may even be harmful. In the study, when scientists investigated the effects of ketogenic diets on a variety of cancer mice in the absence of
PI3K inhibitors, they found that ketogenic diets had little effect on tumors and led to the development of some leukemia more rapidly.
The next plan
Dr. Cantley said any drug targeting
PI3K might not work unless patients can maintain hypoglycemia through diet or drugs. Next, they hope to investigate whether the combination of FDA-approved intravenous PI3K inhibitors and ketogenic diets (especially prepared by nutritionists) is safe for breast, endometrial, leukemia or lymphoma patients and can improve treatment outcomes.
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