The ketogenic diet for the treatment of malignant glioma.
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ABSTRACT:
SUBMITTER: Woolf EC
PROVIDER: S-EPMC4274070 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
Publications
The ketogenic diet for the treatment of malignant glioma.
Woolf Eric C EC Scheck Adrienne C AC
Journal of lipid research 20140206 1
Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an ...[more]
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Project description:Glioblastoma multiforme is a highly aggressive brain tumor with a poor prognosis, and advances in treatment have led to only marginal increases in overall survival. We and others have shown previously that the therapeutic ketogenic diet (KD) prolongs survival in mouse models of glioma, explained by both direct tumor growth inhibition and suppression of pro-inflammatory microenvironment conditions. The aim of this study is to assess the effects of the KD on the glioma reactive immune response.The GL261-Luc2 intracranial mouse model of glioma was used to investigate the effects of the KD on the tumor-specific immune response. Tumor-infiltrating CD8+ T cells, CD4+ T cells and natural killer (NK) cells were analyzed by flow cytometry. The expression of immune inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) on CD8+ T cells were also analyzed by flow cytometry. Analysis of intracellular cytokine production was used to determine production of IFN, IL-2 and IFN- in tumor-infiltrating CD8+ T and natural killer (NK) cells and IL-10 production by T regulatory cells.We demonstrate that mice fed the KD had increased tumor-reactive innate and adaptive immune responses, including increased cytokine production and cytolysis via tumor-reactive CD8+ T cells. Additionally, we saw that mice maintained on the KD had increased CD4 infiltration, while T regulatory cell numbers stayed consistent. Lastly, mice fed the KD had a significant reduction in immune inhibitory receptor expression as well as decreased inhibitory ligand expression on glioma cells.The KD may work in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression. This evidence suggests that the KD increases tumor-reactive immune responses, and may have implications in combinational treatment approaches.
| S-EPMC4866042 | biostudies-literature
Project description:The Ketogenic Diet (KD) is an effective, alternative treatment for refractory epilepsy. This high fat, low protein and carbohydrate diet mimics the metabolic and hormonal changes that are associated with fasting.To maximize the effectiveness of the KD, each meal is precisely planned, calculated, and weighed to within 0.1 gram for the average three-year duration of treatment. Managing the KD is time-consuming and may deter caretakers and patients from pursuing or continuing this treatment. Thus, we investigated methods of planning KD faster and making the process more portable through mobile applications.Nutritional data was gathered from the United States Department of Agriculture (USDA) Nutrient Database. User selected foods are converted into linear equations with n variables and three constraints: prescribed fat content, prescribed protein content, and prescribed carbohydrate content. Techniques are applied to derive the solutions to the underdetermined system depending on the number of foods chosen.The method was implemented on an iOS device and tested with varieties of foods and different number of foods selected. With each case, the application's constructed meal plan was within 95% precision of the KD requirements.In this study, we attempt to reduce the time needed to calculate a meal by automating the computation of the KD via a linear algebra model. We improve upon previous KD calculators by offering optimal suggestions and incorporating the USDA database. We believe this mobile application will help make the KD and other dietary treatment preparations less time consuming and more convenient.
| S-EPMC5546754 | biostudies-other
Project description:BackgroundDiffuse intrinsic pontine glioma (DIPG) is one of the most devastating diseases among children with cancer, thus novel strategies are urgently needed.AimsWe retrospectively evaluated DIPG patients exposed to the carbohydrate restricted ketogenic diet (KD) with regard of feasibility, safety, and overall survival (OS).Methods and resultsSearches of MEDLINE and Embase identified five hits meeting the search criteria (diagnosis of DIPG and exposure to KD). One additional case was identified by contact with experts. Individual patient data were extracted from publications or obtained from investigators. The inclusion criteria for analysis of the data were defined as DIPG patients who were exposed to the KD for ≥3 months. Feasibility, as described in the literature, was the number of patients able to follow the KD for 3 months out of all DIPG patients identified. OS was estimated by the Kaplan-Meier method. Five DIPG patients (males, n = 3; median age 4.4 years; range, 2.5-15 years) meeting the inclusion criteria were identified. Analysis of the available data suggested that the KD is generally relatively well tolerated. Only mild gastro-intestinal complaints, one borderline hypoglycemia (2.4 mmol/L) and one hyperketosis (max 7.2 mmol/L) were observed. Five out of six DIPG patients identified adhered for ≥3 months (median KD duration, 6.5 months; range, 0.25-2 years) to the diet. The median OS was 18.7 months.ConclusionOur study provides evidence that it may be feasible for pediatric DIPG patients to adhere for at least 3 months to KD. In particular cases, diet modifications were done. The clinical outcome and OS appear not to be impacted in a negative way. KD might be proposed as adjuvant therapy when large prospective studies have shown feasibility and safety. Future studies might ideally assess the impact of KD on clinical outcome, quality of life, and efficacy.
| S-EPMC8551993 | biostudies-literature
Project description:BackgroundBased on the hypothesis that cancer cells may not be able to metabolize ketones as efficiently as normal brain cells, the ketogenic diet (KD) has been proposed as a complementary or alternative therapy for treatment of malignant gliomas.Case presentationWe report here our experience in treating two glioma patients with an IRB-approved energy-restricted ketogenic diet (ERKD) protocol as monotherapy and review the literature on KD therapy for human glioma patients. An ERKD protocol was used in this pilot clinical study. In addition to the two patients who enrolled in this study, we also reviewed findings from 30 other patients, including 5 patients from case reports, 19 patients from a clinical trial reported by Rieger and 6 patients described by Champ. A total of 32 glioma patients have been treated using several different KD protocols as adjunctive/complementary therapy. The two patients who enrolled in our ERKD pilot study were monitored with twice daily measurements of blood glucose and ketones and daily weights. However, both patients showed tumor progression while on the ERKD therapy. Immunohistochemistry reactions showed that their tumors had tissue expression of at least one of the two critical mitochondrial ketolytic enzymes (succinyl CoA: 3-oxoacid CoA transferase, beta-3-hydroxybutyrate dehydrogenase 1). The other 30 glioma patients in the literature were treated with several different KD protocols with varying responses. Prolonged remissions ranging from more than 5 years to 4 months were reported in the case reports. Only one of these patients was treated using KD as monotherapy. The best responses reported in the more recent patient series were stable disease for approximately 6 weeks. No major side effects due to KD have been reported in any of these patients.ConclusionsWe conclude that 1. KD is safe and without major side effects; 2. ketosis can be induced using customary foods; 3. treatment with KD may be effective in controlling the progression of some gliomas; and 4. further studies are needed to determine factors that influence the effectiveness of KD, whether as a monotherapy, or as adjunctive or supplemental therapy in treating glioma patients.Trial registrationClinicalTrials.gov# NCT01535911.
| S-EPMC4371612 | biostudies-literature
Project description:BackgroundMalignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells. In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG).MethodsAdult mice were implanted orthotopically with the malignant brain tumors and KetoCal was administered to the mice in either unrestricted amounts or in restricted amounts to reduce total caloric intake according to the manufacturers recommendation for children with refractory epilepsy. The effects KetoCal on tumor growth, vascularity, and mouse survival were compared with that of an unrestricted high carbohydrate standard diet.ResultsKetoCal administered in restricted amounts significantly decreased the intracerebral growth of the CT-2A and U87-MG tumors by about 65% and 35%, respectively, and significantly enhanced health and survival relative to that of the control groups receiving the standard low fat/high carbohydrate diet. The restricted KetoCal diet reduced plasma glucose levels while elevating plasma ketone body (beta-hydroxybutyrate) levels. Tumor microvessel density was less in the calorically restricted KetoCal groups than in the calorically unrestricted control groups. Moreover, gene expression for the mitochondrial enzymes, beta-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-ketoacid CoA transferase, was lower in the tumors than in the contralateral normal brain suggesting that these brain tumors have reduced ability to metabolize ketone bodies for energy.ConclusionThe results indicate that KetoCal has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts. The therapeutic effect of KetoCal for brain cancer management was due largely to the reduction of total caloric content, which reduces circulating glucose required for rapid tumor growth. A dependency on glucose for energy together with defects in ketone body metabolism largely account for why the brain tumors grow minimally on either a ketogenic-restricted diet or on a standard-restricted diet. Genes for ketone body metabolism should be useful for screening brain tumors that could be targeted with calorically restricted high fat/low carbohydrate ketogenic diets. This preclinical study indicates that restricted KetoCal is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer.
| S-EPMC1819381 | biostudies-literature
Project description:This review discusses the effects and mechanisms of a ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, mediumprotein, and low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota-gut-brain axis. It also highlights the clinical evidence for the effects of the ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of the ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.
| S-EPMC9890290 | biostudies-literature
Project description:BackgroundRecent studies in animal models, based on the hypothesis that malignant glioma cells are more dependent on glycolysis for energy generation, have shown promising results using ketogenic diet (KD) therapy as an alternative treatment strategy for malignant glioma, effectively starving glioma cells while providing ketone bodies as an energy source for normal neurons and glial cells. In order to test this treatment strategy in humans, we investigated the relative expression of several key enzymes involved in ketolytic and glycolytic metabolism in human anaplastic glioma (WHO grade III) and glioblastoma (GBM, WHO grade IV).MethodsImmunohistochemistry was performed on formalin fixed paraffin embedded sections from 22 brain biopsies (17 GBM, 3 anaplastic astrocytoma and 2 anaplastic oligoastrocytoma) using antibodies raised against glycolytic and ketolytic enzymes. The glycolytic enzymes included hexokinase-II (HK2) and pyruvate kinase M2 isoform (PKM2). The ketone body metabolic enzymes included: succinyl CoA: 3-oxoacid CoA transferase (OXCT1), 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and BDH2), and acetyl-CoA acetyltransferase 1 (ACAT1). The immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: POS (>20%), LOW (5-20%), and very low (VLOW) (<5%). Focal non-neoplastic "normal" brain tissue within the biopsy specimens served as internal controls.ResultsThe rate limiting mitochondrial ketolytic enzymes (OXCT1 and BDH1) were either LOW or VLOW, concordantly in 14 of the 17 GBMs and in 1 of 5 anaplastic gliomas, whereas at least one of the glycolytic enzymes was POS in 13 of these 17 GBMs and all 5 anaplastic gliomas. Cytosolic BDH2 and mitochondrial ACTAT1 were, surprisingly, POS in most of these tumors.ConclusionOur results showing that malignant gliomas have differential expression of ketolytic and glycolytic enzymes are consistent with previous studies that have shown that these are genetically heterogeneous tumors. It seems reasonable to hypothesize that patients with low or very low expression of key ketolytic enzymes in their malignant gliomas may respond better to the KD therapy than those patients with positive expression of these enzymes. Further studies in animal models and/or a large-scale clinical trial would be needed to test this hypothesis.
| S-EPMC3707813 | biostudies-literature
Project description:The ketogenic diet (KD) was initially used in 1920 for drug-resistant epileptic patients. From this point onward, ketogenic diets became a pivotal part of nutritional therapy research. To date, KD has shown therapeutic potential in many pathologies such as Alzheimer's disease, Parkinson's disease, autism, brain cancers, and multiple sclerosis. Although KD is now an adjuvant therapy for certain diseases, its effectiveness as an antitumor nutritional therapy is still an ongoing debate, especially in Neuroblastoma. Neuroblastoma is the most common extra-cranial solid tumor in children and is metastatic at initial presentation in more than half of the cases. Although Neuroblastoma can be managed by surgery, chemotherapy, immunotherapy, and radiotherapy, its 5-year survival rate in children remains below 40%. Earlier studies have proposed the ketogenic diet as a possible adjuvant therapy for patients undergoing treatment for Neuroblastoma. In this study, we seek to review the possible roles of KD in the treatment of Neuroblastoma.
| S-EPMC9909060 | biostudies-literature
Project description:BackgroundEven in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells.MethodsTo investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model.ResultsThe ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival.ConclusionIn summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways.
| S-EPMC3199865 | biostudies-literature
Project description:Malignant glioma is the most common primary brain tumor and carries a grim prognosis, with a median survival of just over 14 months. Given the poor outcomes with standard-of-care treatments, novel treatment strategies are needed. The concept of virotherapy for the treatment of malignant tumors dates back more than a century and can be divided into replication-competent oncolytic viruses and replication-deficient viral vectors. Oncolytic viruses are designed to selectively target, infect, and replicate in tumor cells, while sparing surrounding normal brain. A host of oncolytic viruses has been evaluated in early phase human trials with promising safety results, but none has progressed to phase III trials. Despite the 25 years that has passed since the initial publication of genetically engineered oncolytic viruses for the treatment of glioma, much remains to be learned about the use of this therapy, including its mechanism of action, optimal treatment paradigm, appropriate targets, and integration with adjuvant agents. Oncolytic viral therapy for glioma remains promising and will undoubtedly impact the future of patient care.
| S-EPMC5398989 | biostudies-literature