| 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 various cancers. ) anti-cancer drugs have not achieved the expected effect." At the same time, the study proposes a feasible strategy that is expected to enhance the anti-cancer potential of such therapies. |
| The R&D dilemma of targeting PI3K |
| The frequent occurrence of PI3K mutations makes this gene an attractive target for cancer drugs. Currently, more than 20 therapies that inhibit the PI3K enzyme are in clinical trials, but the results so far have been disappointing. Some patients taking these drugs experience excessively high blood sugar levels, or hyperglycemia. While this condition is usually temporary because the pancreas is able to lower blood sugar by producing more insulin, some patients' blood sugar levels never return to normal, and they have to stop taking the medication. |
| "In theory, if we shut down the PI3K pathway, which promotes cancer cell growth, we should see clinical responses to these drugs," said Benjamin D. Hopkins, Ph.D., the paper's first author. "But the results haven't been what we expected." |
| Elevated 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, It was this 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 performing' |
| After obtaining the above findings, the scientists hoped 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 such as metformin or SGLT2 inhibitors or treated mice with a ketogenic diet. |
| The results showed that 1) it can increase insulin sensitivity Metformin It did not significantly affect glucose or insulin spikes or cellular signaling that promotes tumor growth; 2) it blocked glucose reabsorption in the kidneys. SGLT2 inhibitors Reduced glucose and insulin spikes 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 proved to be the perfect approach. It reduced glycogen stores, so the mice couldn't release glucose in response to the PI3K inhibitor. This suggested that if you could prevent the glucose surge and subsequent insulin response, 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 May 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 targeting PI3K is likely to be ineffective unless patients can 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 approach in humans," said co-corresponding author Siddhartha Mukherjee, PhD, of the University of California, Berkeley. Reprinted from Dingxiangtong |
