| In the paper published on July 4, titled “Suppression of insulin feedback enhances the efficacy of PI3K inhibitors,” a team led by Dr. Lewis C. Cantley discussed “why targeting the insulin-activating enzyme PI3K （ Phosphatidylinositol-3 kinase, PI3K mutations are associated with multiple cancers )'s anti-cancer drugs did not achieve the expected effect." At the same time, the study proposed a feasible strategy that may improve the anti-cancer potential of such therapies. |
| The R&D dilemma of targeting PI3K |
| Frequent PI3K mutations make the gene an attractive target for cancer drugs. More than 20 therapies that inhibit the PI3K enzyme have entered clinical trials, but so far the results have been disappointing. Some patients taking these drugs have experienced excessively high blood sugar levels, or hyperglycemia. This is usually temporary, as the pancreas is able to lower blood sugar by producing more insulin, but in some patients, blood sugar never returns to normal and the drug has to be stopped. |
| "In theory, if we shut down the PI3K pathway that promotes cancer cell growth, we should see clinical responses to this class of drugs in patients, but the results were not what we expected," said Benjamin D. Hopkins, Ph.D., the paper's first author. |
| Increased insulin levels are to blame |
| So, what exactly is the problem? In this study, Dr. Hopkins and his colleagues found that elevated insulin levels reactivated PI3K in pancreatic tumor-bearing mice treated with the PI3K inhibitor Buparlisib. . |
| The authors stated that It was the rebound rise in insulin that saved the tumor from death. Reactivation of PI3K in tumors renders PI3K inhibitors relatively ineffective. |
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| Image source: Hsiao Lab |
| Ketogenic diet 'best performer' |
| After obtaining the above findings, the scientists hope to find a way to help control blood sugar and insulin levels. In subsequent experiments, in addition to PI3K inhibitors, they also added diabetes drugs metformin or SGLT2 inhibitors or ketogenic diets to treat mice. |
| The results showed that 1) Metformin It did not have much effect on glucose or insulin spikes or on cellular signals that promote tumor growth; 2) it blocked glucose reabsorption in the kidneys SGLT2 inhibitors Reduced glucose and insulin peaks and tumor growth signals; 3) A drug that has been used clinically for about 40 years to control insulin levels Ketogenic Diet In preventing glucose and insulin surges and inhibiting tumor growth signals Do the best . |
| "The ketogenic diet turned out to be the perfect approach. It reduced glycogen stores so the mice could not release glucose in response to the PI3K inhibitor. This suggested that if you could prevent the glucose surge and subsequent insulin feedback, you could make PI3K inhibitors more effective in controlling cancer growth," explained Dr. Hopkins. |
| However, Dr. Hopkins warn , Ketogenic diet alone does not necessarily help control cancer growth, and in some cases, it may even Can be harmful When the scientists investigated the effects of a ketogenic diet in mice with various cancers in the absence of a PI3K inhibitor, they found that the diet had little effect on tumors and caused some leukemias to develop more rapidly. |
| Next steps |
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| Dr. Lewis Cantley. Photo credit Stephanie Diani |
| Dr. Cantley said any drug that targets PI3K is likely to be ineffective unless patients are able to maintain low blood sugar levels through diet or medication. Next, they hope to investigate whether combining an FDA-approved intravenous PI3K inhibitor with a ketogenic diet (specially prepared by a nutritionist) is safe and improves treatment outcomes for patients with breast cancer, endometrial cancer, leukemia, or lymphoma. |
| This research represents a truly innovative approach to cancer therapy. For decades, we have been trying to alter human metabolism to make cancer cells more sensitive to chemotherapy or targeted drugs. We are very excited to try this therapeutic avenue in humans,” concluded co-corresponding author Siddhartha Mukherjee, PhD. Reprinted from Dingxiangtong |
