A study, published in the journal Nature, found a strategy to boost the tumour-killing potential of therapies targeted on the insulin-activated enzyme, phosphatidylinositol-3 kinase (PI3K) – a family of enzymes involved in cellular functions such as cell growth, proliferation and differentiation. “Any drug that targets PI3K may not be effective unless patients can maintain low blood sugar levels through diet or medication. We demonstrated that if we keep insulin down with the ketogenic diet, it dramatically improves the effectiveness of these cancer drugs,” said Lewis C Cantley from Weill Cornell Medicine in the US.
Some of the most common genetic mutations seen in cancerous tumours affect PI3K. The frequency of mutations in the gene has made it an appealing target for cancer drugs, and more than 20 therapies that inhibit the PI3K enzyme have entered into clinical trials. However, the results of these trials so far have not been very promising. Some patients taking these drugs develop hyperglycemia – excessively high levels of blood sugar – which is often temporary, because the pancreas compensate by producing more insulin.
Some patients’ blood sugar levels do not return to normal and they must stop taking the drugs, the researchers said. “This study represents a truly innovative approach to cancer. For decades, we have been trying to alter human metabolism to make cancer cells more sensitive to chemotherapy or targeted drugs,said Siddhartha Mukherjee, an oncologist from Columbia University Irving Medical Center in the US. The fact that this drug itself was enabling a kind of resistance – at least in animal models – comes as a total surprise. We are excited to try this approach in humans,” he said.
To accentuate the effectiveness of the existing therapies, the scientists treated mice with the drugs used to treat diabetes and a ketogenic diet. While the diabetes drugs did not have much effect on the mice, , the ketogenic diet, which has been used in the clinic for about four decades to control insulin levels, did the best job at preventing glucose and insulin spikes and tamping down tumour growth signals. “The ketogenic diet turned out to be the perfect approach. It reduced glycogen stores, so the mice could not release glucose in response to PI3K inhibition, said Benjamin D Hopkins from Weill Cornell Medicine.
“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,” he said. The researchers, however, cautioned that the ketogenic diet alone may not necessarily help control cancer growth and in some cases may even be harmful, like in cases of some leukemias. “We have to make sure there is not some unanticipated toxicity,” Cantley added.