Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

Cortez, Natalia E.; Mackenzie, Gerardo G.

doi:10.3390/nu13093202

Cited by 21 publications

(19 citation statements)

References 154 publications

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“…The ketogenic diet has been suggested as a treatment for a wide range of medical conditions, including migraines (17), epilepsy (18), multiple sclerosis ( 19), Alzheimer's disease (20), diabetes (21), aging (22), cancer (23), and cancer associated cachexia (24). One of the primary mechanisms underlying the purported benefits of the ketogenic diet is the switch from glucose as a primary fuel to fatty acids and ketone bodies.…”

Section: Discussionmentioning

confidence: 99%

Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer

et al. 2022

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Cachexia is a debilitating comorbidity affecting many lung cancer patients. We have previously found that cachectic mice with lung cancer have reduced serum ketone body levels due to low PPARα activity in the liver. Restoring hepatic PPARα activity with fenofibrate increased circulating ketones and delayed muscle and white adipose tissue wasting. We hypothesized that the loss of circulating ketones plays a pathophysiologic role in cachexia and performed two dietary intervention studies to test this hypothesis. In the first study, male and female mice were randomized to consume either a very low carbohydrate, ketogenic diet (KD) or normal chow (NC) after undergoing tumor induction. The KD successfully restored serum ketone levels and decreased blood glucose in cachectic mice but did not improve body weight maintenance or survival. In fact, there was a trend for the KD to worsen survival in male but not in female mice. In the second study, we compounded a ketone ester supplement into the NC diet (KE) and randomized tumor-bearing mice to KE or NC after tumor induction. We confirmed that KE was able to acutely and chronically increase ketone body abundance in the serum compared to NC. However, the restoration of ketones in the circulation was not able to improve body weight maintenance or survival in male or female mice with lung cancer. Finally, we investigated PPARα activity in the liver of mice fed KE and NC and found that animals fed a ketone ester supplement showed a significant increase in mRNA expression of several PPARα targets. These data negate our initial hypothesis and suggest that restoring ketone body availability in the circulation of mice with lung cancer does not alter cachexia development or improve survival, despite increasing hepatic PPARα activity.

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Section: Discussionmentioning

confidence: 99%

Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer

et al. 2022

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“…Pancreatic cancer is one of the malignant tumors of the digestive system with the highest mortality, accounting for the fourth place in the cancer-related mortality [ 1 , 2 ]. In recent years, epidemiology has found that the number of new pancreatic cancer cases in both male and female is increasing [ 3 , 4 ]. In the USA, the number of new malignant tumors ranks 10th in men and 9th in women among all tumors [ 5 ], and in China, the number ranks 7th in men and 11th in women [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical Study of Anti-PD-1 Immunotherapy Combined with Gemcitabine Chemotherapy in Multiline Treatment of Advanced Pancreatic Cancer

Liu

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. This study aimed to investigate the efficacy and safety of anti-PD-1 immunotherapy combined with gemcitabine chemotherapy in multiline treatment of advanced pancreatic cancer. Methods. A retrospective analysis was performed on the clinical data of 32 patients with advanced pancreatic cancer treated with sintilimab regimen from January 2019 to December 2021 in our hospital. All patients were followed up until death or April 2022, in the form of outpatient, in-hospital review, or telephone follow-up. Follow-up content included routine blood, liver and kidney functions, tumor markers, plain or enhanced abdominal CT, and abdominal MRI examinations. Clinical efficacy was evaluated according to mRECIST criteria, and the severity of adverse effects was evaluated according to American Institute for Cancer Research (AICR) Standard Term for Adverse Events, Version 5.0. Results. During treatment, the dosage of sintilimab was halved in 2 patients due to adverse reactions. All patients were treated with sintilimab for 1~10 times, with an average of 6 ± 4 times. The total response rate (ORR) and disease control rate (DCR) were 6.25% and 12.50% and 25.00% and 37.50%, respectively, after 1 and 3 months of treatment. The mean follow-up time of 32 patients was 1-12 months, and the median follow-up time was 4 ± 3 months. By the end point of follow-up, a total of 25 patients died, and the median progression-free survival (PFS) was 3.8 (95% CI (1.85-5.63)) months. The median overall survival (OS) was 5.1 months (95% CI (3.63~7.68). After treatment, the levels of tumor markers CA125, CEA and CA199 were partly decreased compared with those before treatment (all P < 0.001 ). After treatment, the blood routine indexes d-dimer, CRP (C-reactive protein), NLR (neutral granulocyte to lymphocyte ratio), and MLR (monocyte to lymphocyte ratio) decreased compared with those before treatment. In 32 patients with advanced pancreatic cancer, the adverse reactions with an incidence more than 10% included fatigue, rash, hypothyroidism, hyperuricemia, and renal insufficiency. Only 2 patients showed grade 3 fatigue symptom, and all the others showed no adverse reactions of grades 3~5. In this study, all patients’ adverse reactions were relieved after symptomatic treatment. Conclusion. Gemcitabine chemotherapy in multiline treatment of advanced pancreatic cancer with sintilimab can achieve certain clinical benefits without serious adverse reactions.

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“…Multiple cellular mechanisms might explain the beneficial effects of a KD in tumor growth. These include anti-inflammatory, anti-angiogenesis, cell metabolism and epigenetic effects, as well as modulation of the microbiome (15). Unfortunately, many of these studies were performed using xenograft models of pancreatic cancer, which do not closely recapitulate human PDAC, so their clinical significance are limited (16).…”

Section: Introductionmentioning

confidence: 99%

A Ketogenic Diet in Combination with Gemcitabine Increases Survival in Pancreatic Cancer KPC Mice

Cortez

Lanzi

Hong

et al. 2022

Cancer Research Communications

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Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.

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Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

Cited by 21 publications

References 154 publications

Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer

Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer

Clinical Study of Anti-PD-1 Immunotherapy Combined with Gemcitabine Chemotherapy in Multiline Treatment of Advanced Pancreatic Cancer

A Ketogenic Diet in Combination with Gemcitabine Increases Survival in Pancreatic Cancer KPC Mice

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