Several months before my surgical procedure, a cancer patient asked me whether she should change her diet. She had lost her appetite. One nutritionist had advised her to start consuming highly caloric, sugar-loaded drinks to maintain her body weight. But, she worried, what if the sugar ended up “feeding” her cancer? Her anxiety was built on nearly eight decades of science: In the 1920s, Otto Warburg, a German physiologist, demonstrated that tumor cells, unlike most normal cells, metabolize glucose using alternative pathways to sustain their rapid growth, provoking the idea that sugar might promote tumor growth.
You might therefore expect the medical literature on “sugar feeding cancer” to be rich with deep randomized or prospective studies. Instead, when I searched, I could find only a handful of such trials. In 2012, a team at the Dana-Farber Cancer Institute in Boston divided patients with Stage 3 colon cancer into different groups based on their dietary consumption, and determined their survival and rate of relapse. The study generated provocative data — but far from an open-and-shut case. Patients whose diets consisted of foods with a high glycemic load (a measure of how much blood glucose rises after eating a typical portion of a food) generally had shorter survival than patients with lower glycemic load. But a higher glycemic index (a measure of how much 50 grams of carbohydrate from a food, which may require eating a huge portion, raises blood glucose) or total fructose intake had no significant association with overall survival or relapse.
While the effect of sugar on cancer was being explored in scattered studies, the so-called ketogenic diet, which consists of high fat, moderate protein and low carbohydrate, was also being promoted. It isn’t sugars that are feeding the tumor, the logic runs. It’s insulin — the hormone that is released when glucose enters the blood. By reducing carbohydrates and thus keeping a strong curb on insulin, the keto diet would decrease the insulin exposure of tumor cells, and so restrict tumor growth. Yet the search for “ketogenic diet, randomized study and cancer” in the National Library of Medicine database returned a mere 11 articles. Not one of them reported an effect on a patient’s survival, or relapse.
But what if diet, rather than acting alone, collaborates with a drug to produce an effect on a tumor? In the winter of 2016, I had dinner with Lewis Cantley, director of the Meyer Cancer Center at Weill Cornell Medicine. Decades ago, Cantley discovered an enzyme named PI3 kinase, which regulates the growth and survival of cells in the presence of nutrients. By inhibiting this enzyme using novel drugs, researchers had hoped to target the signals used by tumor cells to grow, thus “starving” the cancer. But the drugs designed thus far were only marginally effective. Why, we wondered over salmon teriyaki in a nondescript Upper East Side joint, might blocking such a central hub of growth activity have had only a modest effect on tumor growth?
The trials gave us a crucial, obvious clue that we had missed: Many patients had become diabetic, a phenomenon seen as a side effect of the drug that had been ignored. Perhaps the drug wasn’t just providing a “starvationlike” signal only to the tumor cells, we speculated. As most drugs do, the molecule circulated through the entire body of the patient and also acted on the liver, which sensed the same starvationlike signal and, as a reflexive response, sent glucose soaring into the blood. The glucose, in turn, most likely incited insulin release in the pancreas. And some patients treated with the medicine returned to the clinic with sky-high levels of glucose and insulin — in essence, in the throes of drug-induced diabetes.
Cantley wondered whether the additional insulin was reactivating the signals within the tumor cells that had been shut off by the PI3 kinase inhibitor, and so allowing the cells to survive — in effect, undoing all the good being done by the drug. On a paper napkin borrowed from the waiter, he drew out a scheme to outwit this vicious cycle. What if we cut off all extra insulin released, by putting patients on a low-carb, ketogenic diet while on the drug? It would be a novel kind of trial — one in which diet itself would become a drug, or a co-drug, with the PI3 kinase inhibitors.
Between 2016 and 2018, postdoctoral researchers in Cantley’s laboratory and mine established that this strategy worked on several mouse cancers, and on human cancers implanted into mice. By 2019, working with clinicians at Columbia, Cornell and Memorial Sloan Kettering, we hope to begin a study in humans with lymphomas, endometrial cancer and breast cancer, to use ketogenic diets in concert with the PI3 kinase inhibitors. (In the meantime, a host of other studies have also demonstrated that other diets could potently modulate the effects of targeted therapies on cancers in mouse models.)
But the experiments on mice also warned us of an important pitfall of such an approach. While the “drug plus diet” model worked on experimental mouse and human cancers, the ketogenic diet had a limited effect by itself. For some cancers in the mouse models, the keto diet alone kept the tumor growth at bay. But for others, like some leukemias implanted into mice, the diet alone accelerated the cancer, while the drug-plus-diet approach slowed it down.
We published this data in the scientific journal Nature early this year. I sent out a tweet with the results, emphasizing that the human trial was about to be started, and that the keto diet alone might have a negative effect on some tumors — in essence, a “folks, don’t try this at home” message. The response over social media was unexpected — brisk, vicious, angry, suspicious and, at times, funny. “Keto is pure hype,” one responder wrote. Another countered: “Who is supporting you? Big Kale?”
