Dr. Cantley was a professor at Tufts University School of Medicine in the '80s when he identified a previously unknown enzyme, phosphoinositide-3-kinase, or PI3K, that would turn out to be a sort of master switch for cancer. The protein's normal function is to alert cells to the presence of insulin, prompting them to pump in glucose, cells' metabolic fuel. This signaling pathway is crucial to cells' growth, proliferation and survival, so it makes sense that malfunctions can cause serious problems. If the pathway runs too slowly, the body becomes insulin-resistant and cells fail to take up enough glucose: this is Type II diabetes. In cancer, however, the pathway shifts into high gear, providing tumors with an overabundant supply of glucose, which drives their growth.
It turned out that the gene that encodes PI3K is the most frequently mutated cancer-promoting gene in humans—and in the years since Dr. Cantley's revolutionary discovery, it has been implicated in as many as 80 percent of cancers, including those of the breast, brain and bladder. The pathway has also served as a target for new drugs, including the breakthrough lymphoma and leukemia drug idelalisib, which in 2014 became the first PI3K inhibitor to be approved by the FDA. Dr. Cantley came to Weill Cornell Medicine in 2012, his scientific reputation well-established; he has won a host of prestigious international awards, and his name comes up frequently when colleagues speculate about future Nobel laureates. Since setting up his lab at Weill Cornell Medicine, he has continued to investigate the role of PI3K.
One of oncology's major frustrations is that some drugs that aim to inhibit PI3K have been less successful in clinical trials than originally hoped. Blocking the enzyme should impede the signals that allow cancer cells to take in the high levels of glucose they need to survive, but it doesn't always work that way. In many patients, PI3K inhibitors cause blood sugar to spike, suggesting that the drugs meant to starve tumors were telling the liver that the body itself was starving, too. In response, the liver—which stores extra glucose in the form of a compound called glycogen—was sending too much sugar into the blood, which triggered the pancreas to release excess insulin. Meanwhile, these patients' tumors continued to grow.
Dr. Cantley and his colleagues wondered whether the excess insulin might be countering the effect of the drugs by reactivating the PI3K pathway in the cancer cells. They theorized that a diet very low in carbohydrates—limiting both sugar and starch, which breaks down into simple sugars in the body—would prevent spikes in blood sugar and might help the drug do its work, starving the tumor while the patient's body fueled itself with fat and protein instead, a state called ketosis. So researchers in Dr. Cantley's lab, including instructor in medicine Dr. Benjamin Hopkins, worked with colleagues at Columbia University Irving Medical Center and NewYork-Presbyterian to test the hypothesis.
Using mice that had been genetically engineered to develop pancreatic, bladder, endometrial and breast cancers and treated with a new PI3K inhibitor (which is currently in clinical trials), they demonstrated that spikes of insulin did indeed reactivate the pathway in tumors, countering the anti-cancer effect of the drug. But when the researchers severely restricted the mice's carbohydrate intake, putting them on what's known as a ketogenic diet in addition to the medication, the tumors shrank. (Adding a diabetes drug meant to lower blood sugar levels also helped, but the effects of the diet in conjunction with the PI3K inhibitor were more dramatic.) The encouraging results were published in the journal Nature in July 2018 with Dr. Hopkins as lead author. "The mutations to the PI3K pathway that cause cancer also enhance the ability of insulin to activate the enzyme," Dr. Cantley explains. "Our preclinical research suggests that if somewhere in your body you have one of these PI3K mutations and you eat a lot of rapid-release carbohydrates, every time your insulin goes up, it will drive the growth of a tumor. The evidence really suggests that if you have cancer, the sugar you're eating may be making it grow faster."
Is Ketosis Key?
The Internet is full of diet advice, and among today's hottest fads is a low-carb regimen popularly known as "keto." It was the most Googled diet trend of 2018, a popular weight loss strategy among celebrities like reality TV star Kourtney Kardashian and basketball icon Lebron James, who sometimes refer to it as "paleo," for its supposed resemblance to the diets of our Paleolithic ancestors. But that's not what clinicians or researchers mean when they talk about a ketogenic diet, explains Dr. Katie Hootman, a registered dietician and director of the Metabolic Research Unit at Weill Cornell Medicine's Clinical and Translational Science Center (CTSC). "The diets on the internet tend to be way too high in protein," she says. "There is a pretty big difference between that and a clinical ketogenic diet, one that's actually intended to get the patient into ketosis."
Ketosis, Dr. Hootman explains, is a state in which the body relies on the metabolism of fat as the primary fuel to meet energy demands, rather than glucose, cells' preferred source of energy. From the breakdown of fat, the liver circulates molecules called ketone bodies, which cells use as fuel until carbohydrates become abundant again. This metabolic process evolved to help mammals survive food shortages, but in a clinical context it has been used since the early 20th century to reduce seizures in people with epilepsy. A few studies in the late 20th and early 21st centuries suggested a ketogenic diet might also be helpful against some forms of cancer, but it is only recently that researchers have studied its usefulness in conjunction with anti-cancer drugs. Among the clearest evidence is the Dr. Cantley Lab's mouse study, which Dr. Hootman is now helping to translate to human patients.
In the meantime, Dr. Cantley—ever the anti-sugar evangelist—adds that limiting sweets certainly couldn't hurt. Eating less sugar, he says, is clearly beneficial. "It'll help you in so many different ways, with so many different diseases," he says. "And once you don't have that addiction anymore, it's actually quite easy. After all, I've had no trouble doing it for 40 years."
Dr. Lewis Cantley has a very simple rule, he says. "I eat fruit, but I don't eat anything that has sugar added to it. And I guarantee everybody would be better off if they ate zero sugar."