The findings of a new study suggest that a ketogenic diet—which is low in carbohydrates and protein, but high in fat—helps to kill pancreatic cancer cells when combined with a triple-drug therapy developed by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope.
In laboratory experiments, the ketogenic diet decreased glucose (sugar) levels in the tumor, suggesting the diet helped starve the cancer. In addition, this diet elevated ketone bodies produced by the liver, which put additional stress on the cancer cells. The study published in the journal Med.
By destabilizing the cancer cells, the ketogenic diet created a microenvironment in which the triple-drug therapy designed by TGen – a combination of gemcitabine, nab-paclitaxel and cisplatin – was more effective at knocking out the tumor, according to the study.
“By limiting glucose availability, the ketogenic diet may promote chemotherapy efficacy,” said TGen Distinguished Professor Daniel D. Von Hoff, M.D., considered one of the nation’s foremost authorities on pancreatic cancer. Dr. Von Hoff is one of the study authors and designers of the therapy.
Clinical trials at five locations
To test these laboratory findings, researchers initiated a clinical trial of up to 40 patients at five centers nationwide: HonorHealth in Scottsdale, USC in Los Angeles, Nuvance Health in Connecticut, Atlantic Health System in New Jersey, and South Texas Accelerated Research Therapeutics in San Antonio.
The clinical trial will test whether adding a ketogenic diet to the triple-drug therapy will increase overall survival in patients with pancreatic cancer.
This clinical trial began in late 2020 and is anticipated to continue to accrue patients through June 2023. Patients will be randomly assigned to either receive the triple-drug regimen while on a standard diet, while the other half will receive a ketogenic diet and the triple-drug therapy. The dietary aspects of the study are being carefully monitored.
“Our laboratory experiments show that a ketogenic diet changes pancreatic cancer metabolism and its response to chemotherapy,” said Haiyong Han, Ph.D., a Professor in TGen’s Molecular Medicine Division, and one of the study authors and a designer of the study’s experiments.
Cells require chemical energy in the form of ATP to maintain their function. Metabolism generates ATP both anaerobically, through glycolysis, and aerobically, through NADH and oxidative phosphorylation.
Cells have a finite respiratory capacity, determined by the number of healthy mitochondria and the availability of oxygen. In other words, there is a limit to how much NADH cells can handle. When this limit is approached, NADH and reduced respiratory chain complexes accumulate, leading to reactive oxygen species (ROS).1 This redox stress can be catastrophic in patients with genetic mitochondrial disorders, and may also occur in cells where respiration is impaired for other reasons—for example, oxygen deprivation as often occurs in tumors.2, 3, 4, 5
Cells employ a variety of mechanisms to avoid excessive NADH accumulation. One is lactate excretion, with ATP generated through glycolysis. This requires an adequate supply of glucose, either from internal stores (glycogen) or the microenvironment, which is often glucose depleted in tumors.6,7 Another is feedback inhibition of mitochondrial NADH-generating enzymes, such as pyruvate dehydrogenase.8, 9, 10
Using these approaches, cultured cells with impaired electron transport chain function can survive but cannot proliferate in standard medium, in part because NADH buildup in mitochondria blocks the synthesis of aspartate and pyrimidines.8,9,11 Growth can be restored by providing pyruvate, whose reduction to lactate clears extra NADH. Within the body, pyruvate is available in the circulation. Rapid exchange between circulating lactate/pyruvate and tissue NADH/NAD has been hypothesized to buffer local redox perturbations, and whole-body reductive stress can be mitigated by injection of an engineered enzyme, LOXCAT, which converts circulating lactate into pyruvate.12
Pancreatic ductal adenocarcinoma (PDAC) tumors are characterized by stromal fibrosis that limits blood flow. They are hypoxic, nutrient-deprived, and have lower glucose and higher lactate levels than surrounding pancreatic tissue.13,14 Somehow, despite this harsh metabolic environment, PDAC tumors grow irrepressibly. Diagnosis typically occurs after metastasis with associated poor prognosis. Recently, augmentation of the most common chemotherapy regimen of gemcitabine and albumin-bound nanoparticle paclitaxel (nab-paclitaxel) with cisplatin led to median survival of 16 months, a step forward but still terribly short.15, 16, 17 Accordingly, strategies to augment PDAC treatment are desperately needed.
One possibility is dietary manipulation. Diets lacking in serine/glycine or methionine have shown efficacy in murine colorectal cancer models.18,19 Fasting or fasting-mimicking diet enhanced therapeutic activity of endocrine therapeutics in hormone-receptor-positive breast tumor models20 and, in a phase II study, a fasting-mimicking diet showed favorable pathological and radiographic trends when combined with cytotoxic chemotherapy for breast cancer.21
A ketogenic diet—very low carbohydrate, low protein, and high fat—mimics several aspects of fasting without calorie restriction. Even in the fed state, glucose and insulin are low and ketone bodies (3-hydroxybutyrate [3HB], acetoacetate, and acetone) are high. The ketogenic diet has attracted attention as a potential means of enhancing cancer treatment.22, 23, 24, 25 Proposed mechanisms include suppression of pro-tumorigenic insulin signaling, depletion of glucose as a preferred tumor fuel, imbalances between saturated and unsaturated fatty acids, and antitumor effects of ketone bodies, which may potentially include reductive stress or histone deacetylation inhibition.26, 27, 28
Although phosphatidylinositol 3-kinase (PI3K) inhibitors have not shown utility in pancreatic cancer, Hopkins et al. showed that these inhibitors are effective in pancreatic cancer mouse models when combined with the ketogenic diet.29 In this context, the ketogenic diet prevents the PI3K inhibitor-induced hyperglycemia and associated hyperinsulinemia which otherwise tend to override the pharmacological PI3K inhibition, resulting in effective blockade of both PI3K signaling and tumor growth.
Here, we test the impact of a ketogenic diet (with roughly balanced saturated versus unsaturated fatty acid composition) on the growth of murine pancreatic KPC tumors (spontaneous in pancreas or passaged as flank allograft). While ineffective on its own, when combined with the current standard-of-care chemotherapy for PDAC, the ketogenic diet impairs tumor growth and significantly prolongs survival. The tumor growth impairment is associated with glucose depletion, altered tricarboxylic acid (TCA) substrate usage, and NADH elevation.
reference link :https://www.cell.com/med/fulltext/S2666-6340(21)00409-8
More information: Lifeng Yang et al, Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth, Med (2022). DOI: 10.1016/j.medj.2021.12.008