With Joshua Rabinowitz, MD, PhD, of Princeton University & Ludwig Princeton Branch
By Sarah DiGiulio
Could following a certain diet help cancer treatment work better? For patients with pancreatic cancer undergoing chemotherapy, the ketogenic diet might, according to data published earlier this year in the journal Med (2022; doi: 10.1016/j.medj.2021.12.008). The preclinical trial found that a ketogenic diet (high-fat, modest protein, and very low carbohydrate intake) with chemotherapy tripled survival time compared with chemotherapy alone in mouse models of pancreatic ductal adenocarcinoma. The research also shed light on some the mechanisms that explain why the ketogenic diet might enhance the anti-cancer effects of chemotherapy.
In an interview with Oncology Timesstudy coauthor Joshua Rabinowitz, MD, PhD, Director of the Ludwig Princeton Branch and Professor in the Department of Chemistry and the Lewis-Sigler Institute for Integrative Genomics at Princeton University, explained why these findings are important.
1. Why did you and your team suspect that the ketogenic diet might enhance the effects of chemotherapy in pancreatic cancer?
“We’ve known for a while that cancer is an avid glucose user. And we’ve learned that a key driver of this activation is the PI3-kinase pathway, which can happen two ways: through mutations of enzymes in the pathway or through insulin signaling.
“There’s also new empirical evidence from several labs that had shown evidence for combining either fasting or ketogenic diet with chemotherapy. Previous work shows, for example, that a very profound fast of 2 full days in a mouse (which is the equivalent of about a 2-week fast in a person) made chemotherapy work better (Sci Transl Med 2012; doi: 10.1126/scitranslmed.3003293).
“So this was a strong motivation for us to test the ketogenic diet in cancer. One of the key features of the ketogenic diet is that it mimics a lot of metabolic and hormonal events that occur during fasting, but while allowing full nutrient intake.”
2. What were the most significant findings from your work?
“The most exciting aspect of the study was the therapeutic benefit for chemotherapy in the context of following the ketogenic diet (versus a regular diet) in quite stringent mouse models of pancreatic cancer. We saw therapeutic benefit of the best available chemotherapy for pancreatic cancer was increased about threefold by ketogenic diet.
“Beyond that, we looked at a lot of metabolic and redox parameters—and I think there are two most important findings in terms of the mechanism of the effects.
“First, the tumors are always depleting glucose from the tumor environment (much like you would expect), but this depletion of environmental glucose gets stronger when they’re treated with chemotherapy. So it seems like the chemotherapy is driving glucose usage—perhaps for a subset of tumor cells to survive the chemotherapy. Ketogenic diet makes this glucose less available.
“The other important mechanistic insight was that chemotherapy tends to induce a more reductive environment in the cell, in particular the cofactor NADH.” [which is the high energy form of the cofactor]. That can lead to reactive oxygen species that damage the cell. It’s problematic for the cancer cell, but good from our perspective [in that it makes it harder for the cancer cells to survive and grow after chemotherapy treatment].
“It’s important to note that we see the benefit beneficial therapeutically when you combine chemotherapy with a ketogenic diet. [Ketogenic diet by itself—without an additional therapy—doesn’t have an effect on cancer]. Ketogenic diet seems to sensitize the tumor—at least in this mouse model—to chemotherapy.”
3. These findings are still somewhat early in that the research has all been done in mice. What’s the next step of your work and showing that you’d see a similar effect in people with pancreatic cancer?
“We’re optimism that we’ll see benefits to human patients. The core mechanistic concepts of insulin suppression, glucose suppression, and redox stress due to ketone body buildup—think of those as the three legs of the stool on which this therapy’s success resides—they’re all equally applicable in mice and humans. At the same time, we know that humans eat a much more complicated diet than mouse chow. There are many variables that may not be properly captured yet in terms of how we translate a diet from mouse to human.
“We do have a multi-center, randomized clinical trial ongoing where patients will receive the best available therapy for pancreas cancer. And then patients are randomized to either follow their normal carbohydrate-containing diet or switch to a ketogenic diet. This is for patients with metastatic pancreas cancer as first-line therapy. We have sites open across the country. It’s going to give us really important answers because it’s going to be the best randomized, clinical trial of a diet-drug combination—full stop—when we complete the trial.
“We know it’s important to patients to have dietary guidelines. That’s the broader mission of this endeavors. I think different types of therapy are going to need prioritization of different aspects of diet. For the community at large, I think it’s important to know that trials are starting to happen that are examining these issues.”