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Could Metabolic Therapy Become a Viable Alternative to the Standard of Care for Managing Glioblastoma?

Published Online: May 8th 2014 Oncology & Hematology Review, 2014;10(1):13–20 DOI: https://doi.org/10.17925/OHR.2014.10.1.13
Authors: Thomas N Seyfried, Jeremy Marsh, Purna Mukherjee, Giulio Zuccoli, Dominic P D’Agostino
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Overview

Little progress has been made in the long-term management of glioblastoma multiforme (GBM) for more than 40 years. The current standard of care (SOC) for GBM involves radiotherapy with concomitant adjuvant temozolomide chemotherapy. Perioperative corticosteroids are also administered to the majority of GBM patients. The current standard treatment strategy for GBM increases availability of glucose (from steroids) and glutamine (from radio-necrosis) in the tumor microenvironment. Emerging evidence indicates that GBM, like most cancers, is a metabolic disease displaying a robust Warburg effect. It is well documented that glucose and glutamine are major metabolic fuels that drive tumor progression. Recent evidence suggests that neoplastic cells with macrophage/microglia properties can contribute to the most invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells as well as for the more rapidly proliferating cancer cells. Metabolic therapy exploits the biological differences between tumor cells and normal cells for the non-toxic targeting of the tumor cells. Studies in preclinical models show that calorie restricted ketogenic diets (KD-R), anti-glycolytic drugs, and hyperbaric oxygen therapy can reduce availability of glucose and glutamine in the tumor microenvironment while enhancing oxidative stress in tumor cells. The predominant ketone body (b-hydroxybutyrate) reduces oxidative stress in normal brain cells. The potential success of metabolic therapy was also seen in human glioma case studies suggesting that this therapeutic strategy could become a viable alternative to the SOC.

Keywords

Glioblastoma, standard of care, metabolic therapy, anti-glycolytic drugs, ketogenic diets, hyperbaric oxygen therapy, Warburg effect

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Glioblastoma Multiforme
Glioblastoma multiforme (GBM) is the most malignant of the primary brain cancers with only about 12 % of patients surviving beyond 36 months (longterm survivors).1–4 Most GBMs are heterogeneous in cellular composition consisting of tumor stem cells, malignantly transformed mesenchymal cells, and host stromal cells; hence, the name ‘glioblastoma multiforme.’5–11 Primary GBM appears to arise de novo, while secondary GBM is thought to arise from low-grade gliomas.7,12,13 The incidence and timing of malignant progression from low-grade glioma to GBM is variable and unpredictable.14 In addition to the neoplastic cell populations, tumor-associated macrophages/ monocytes (TAM) also comprise a significant cell population in GBM sometimes equaling the number of tumor cells.15–20 TAM can indirectly contribute to tumor progression through release of pro-inflammatory and pro-angiogenic factors.16,18,20,21 Neoplastic cells with myeloid/macrophage characteristics (CD68 expression) can also contribute to the sarcomatoid characteristics of GBM.5,11,12,22 We suggested that many cells appearing as TAM within GBM could be neoplastic with properties of macrophages/ microglia.22 Using the secondary structures of Scherer, the neoplastic cells in GBM invade through the neural parenchyma well beyond the main tumor mass, making complete surgical resections exceedingly rare.2,23–26 Although systemic metastasis is rare for GBM, GBM cells can be metastatic if given access to extraneural sites.27–31 Despite extensive analysis from the cancer genome projects, no mutation is known that is unique to the GBM and no genetic alterations are seen in major signaling pathways in about 15 % of GBM.32,33 Moreover, few of the personalized molecular markers available are considered important for GBM analysis or therapy.34 Recent evidence also suggests that the genomic abnormalities seen in cancer cells arise as downstream secondary effects of disturbed energy metabolism and are unlikely to provide useful information for therapeutic treatment strategies for the majority of GBM patients.13,35,36

The Current Standard of Care for Glioblastoma
The current standard of care (SOC) for GBM and many malignant brain cancers includes maximum surgical resection, radiation therapy, and chemotherapy.2,3,37,38 The toxic alkylating agent temozolomide (TMZ) is the most common chemotherapy used for treating GBM. Most GBM patients also receive perioperative corticosteroids (dexamethasone), which are often extended throughout the course of the disease.39,40 There have been no major advances in GBM management for over 50 years, though use of TMZ has produced marginal improvement in patient survival over radiation therapy alone.3,41 Marginal benefits from the use of TMZ are also observed in those GBM patients who express promoter methylation of their DNA-repair enzyme O6-methylguanine DNA methyltransferase (MGMT) gene.42,43

Despite conventional treatments, prognosis remains poor for most patients with high-grade brain tumors (see Figure 1).2–4,37,41,44,45 The optimal therapeutic strategy for recurrent high-grade gliomas is unknown, and an effective SOC does not exist. Re-irradiation together with the anti-angiogenic drug, bevacizumab (Avastin®), is also often offered to some GBM patients with recurrent disease despite the removal of bevacizumab for breast cancer due to toxicity and lack of efficacy by the US Food and Drug Administration (FDA).46–48 Bevacizumab treatment increases progression-free survival in GBM patients, but does not increase overall patient survival.49 It seems that bevacizumab treatment delays the time-to-progression by technically changing the magnetic resonance imaging (MRI) findings. Bevacizumab substantially decreases contrast enhancement on T1-weighted MRI in recurrent GBM compared with high-dose dexamethasone suggesting that the major benefit of bevacizumab is in its anti-edema action. Consequently, bevacizumab appears to act like steroids in reducing edema, but not in killing the most invasive tumor cells.

Do the Current Standard Treatments for Glioblastoma Multiforme Enhance Recurrence and Progression through Effects on Energy Metabolism?
Emerging evidence indicates that cancer is primarily a disease of energy metabolism.35,50 In light of this information it is our view that the current SOC for GBM and other malignant brain cancers could contribute to tumor recurrence and progression through effects on tumor cell metabolism. Our suggestion comes from new information describing how the SOC can enhance the availability of glucose and glutamine within the tumor microenvironment.18,47,51 Glucose and glutamine are major drivers of tumor cell energy metabolism.48,52–54 It is well documented that neurotoxicity from mechanical trauma (surgery), radiation therapy, and chemotherapy, will increase tissue inflammation and glutamate levels.24,55–58 Damage to brain tissue can induce hyperglycolysis and an increased demand for glucose.59 Necrotic brain injury can arise from radiotherapy.60,61 Tumor radiation will also up-regulate the PI3K/Akt signaling pathway, which drives glioma glycolysis and chemotherapeutic drug resistance.62–66 Fatigue is not uncommon in GBM patients that receive the SOC.67,68 Radiation of tissues is known to induce systemic inflammation, which is suggested to underlie the fatigue associated with cancer therapy.69 It is not yet clear if the fatigue seen in some GBM patients might arise in part from brain irradiation or from other toxic effects of SOC. Tissue inflammation also enhances local hypoxia while providing a plethora of growth factors that facilitate angiogenesis and tumor cell rescue.18 Local astrocytes rapidly clear extracellular glutamate, metabolizing it to glutamine for release to neurons.70 In the presence of dead or dying neurons, however, surviving tumor cells and the TAM will use astrocyte-derived glutamine for their energy and growth. TAM also release pro-angiogenic growth factors, which further stimulate tumor progression.18,20,48 Most neoplastic GBM cells are infected with human cytomegalovirus (HCMV), which could further accelerate tumor cell growth through increased metabolism of glucose and glutamine.71,72 In contrast to normal glia that metabolize glutamate to glutamine, Takano and co-workers showed that neoplastic glioma cells secrete glutamate.55 Glioma glutamate secretion is thought to contribute in part to neuronal excitotoxicity and tumor expansion.55 Lawrence and co-workers suggested that survival was better for glioma patients who experienced less neurologic toxicity than for patients who experienced more neurologic toxicity.73 It appears that therapies that enhance neurotoxicity could facilitate GBM progression. This raises the question of whether the current SOC creates a metabolic environment that could promote GBM progression.

In addition to the potential tumor-enhancing effects of radiation and HCMV on GBM energy metabolism, most GBM patients are also given glucocorticoids (dexamethasone).40 Although dexamethasone is given to reduce radiationassociated brain swelling and tumor edema, dexamethasone elevates blood glucose levels.64,74–78 Glucose fuels the Warburg effect as well as serving as a precursor for glutamate synthesis and nucleotide synthesis through the pentose phosphate pathway.35,50,70,79,80 It is not likely that therapies, which elevate blood glucose, will improve patient survival. Indeed, prognosis was considered worse for glioma patients with higher blood glucose levels than in patients with lower glucose levels.81,82 These observations in GBM patients support our original work in a preclinical glioma model.78

Many GBM patients are also treated with anti-angiogenic drugs, such as bevacizumab. These drugs target leaky blood vessels thus enhancing hypoxia and radiation-induced necrosis in the tumor microenvironment. Increased hypoxia will further enhance tumor cell glycolysis and select for those tumor cells with greatest invasive properties.48,83–85 This will be especially advantageous to those tumor cells that arise from macrophage or microglial fusion and are already capable of surviving in hypoxic environments.22,86 Further studies are needed to determine if anti-angiogenic drugs exacerbate radiation-induced necrosis, which could create a more favorable environment for tumor recurrence.87 When viewed together these findings illustrate how the current GBMtreatment strategies could create a microenvironment that facilitates the energy needs of tumor cells and recurrence of the tumor. The process is illustrated in Figure 2.

Although the existing SOC for malignant brain cancer will increase patient survival over the short term (months) compared with the ‘no therapy’ option,88 it is clear from extensive in vitro and in vivo (animal) experiments how this therapeutic strategy could enhance the Warburg effect in surviving tumor cells. Moreover, the malignant phenotype of brain tumor cells that survive radiotherapy is often greater than that of the cells from the original tumor.64 Treatments that increase the Warburg effect in tumor cells will facilitate tumor cell growth and invasion.50 It is not likely that survival will be improved in patients receiving therapies that would increase the Warburg effect. The data from Stupp et al. show that none (0/278) of the patients receiving radiation alone survived, whereas only about 2 % (6/254) of patients receiving radiation and TMZ became long-term survivors (see Figure 1). These findings address the general inadequacy of current therapies in providing long-term management of GBM. The slight improvement of patient survival with TMZ is remarkable in light of recent findings showing that TMZ enhances the number of driver mutations in the tumor tissue.13 How might TMZ improve overall patient survival if the drug is suggested to increase the number of driver mutations in the tumor? Driver mutations are thought to provoke tumor progression by conferring a growth advantage to the most neoplastic cells.32,33,89–91 These findings illustrate the disconnect between driver mutations and tumor progression and further question the gene theory of cancer.35 While GBM is certainly a deadly disease, is it possible that current treatment strategies might make the disease even worse?

Mitochondrial Abnormalities in Malignant Brain Tumors
Although mitochondrial abnormalities are found in all cancers including brain cancer,35,36,92–94 mitochondrial abnormality is not generally recognized as a major cancer hallmark.95 Mitochondrial abnormalities will reduce energy production through oxidative phosphorylation (OxPhos).51,66,92–94,96–103 The ultrastructure of mitochondria in malignant brain tumors differs markedly from the ultrastructure of normal tissue mitochondria.93,98,104 In contrast to normal mitochondria, which contain numerous cristae, mitochondria from GBM tissue samples showed swelling with partial or total cristolysis (see Figure 3). Cristae contain the proteins of the respiratory complexes, and play an essential structural role in facilitating energy production through OxPhos.94,105–107 The structural defects in human glioma mitochondria are also consistent with lipid biochemical defects in murine gliomas. We showed that cardiolipin, the signature phospholipid of the inner mitochondrial membrane, was abnormal in five independently derived mouse brain tumors.108,109 Cardiolipin controls the efficiency of OxPhos, and any alterations in the content or fatty acid composition of cardiolipin will reduce cellular respiration.110–112 In addition to these findings, Poupon and colleagues also indicated that the high glycolytic activity seen in malignant gliomas could arise from mitochondrial structural abnormalities.113 Hence, substantial morphologic and biochemical evidence exists showing that respiratory capacity is defective in gliomas.

The Warburg Effect in Glioblastoma Multiforme
Based on an extensive analysis of human and animal tumors, Otto Warburg first proposed that all cancers arise from irreversible damage to cellular respiration.80,114 As a result, cancer cells increase their capacity to ferment lactate even in the presence of oxygen in order to compensate for their insufficient respiration.80,114 Although confusion has surrounded Warburg’s hypothesis on the origin of tumor cells,115,116 his hypothesis has never been falsified and remains a credible explanation for the origin of cancer.66,117–121 The key points of Warburg’s theory are: 1) insufficient respiration initiates tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to ferment lactate in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible.80,114,122–124 Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as ‘aerobic fermentation’ to highlight the abnormal production of lactate in the presence of oxygen.80,114,122–124 The ‘Warburg effect’ refers to the aerobic fermentation of cancer cells.118,119 Substantial evidence exists showing that malignant gliomas produce lactate.50,125,126 Lactate is the end product of pyruvate fermentation. This would be expected for any tumor cell with quantitative or qualitative abnormalities in mitochondria.

As the result of insufficient respiration, cancer cells must rely on non-oxidative mechanisms to maintain energy balance and viability. Consequently, aerobic fermentation plays a role in producing energy through substrate level phosphorylation in the cytoplasm (glycolysis).51,66,123,127 Besides aerobic fermentation in the cytoplasm, tricarboxylic acid (TCA) cycle substrate level phosphorylation might also produce ATP through non-oxidative metabolism in the mitochondria.35,50,128 It can be difficult to determine, however, the degree to which mitochondrial ATP production arises from coupled respiration or from TCA cycle substrate level phosphorylation.129–132 A protracted reliance on non-oxidative energy metabolism, involving glucose and amino acid fermentation with substrate level phosphorylation, can cause genomic instability and other recognized hallmarks of cancer.51,66,128 Emerging evidence indicates that the function of DNA repair enzymes and the integrity of the nuclear genome are dependent to a large extent on normal respiration and mitochondrial function.133–140 In other words, genomic instability ultimately arises from a protracted insufficiency of OxPhos and is considered a downstream epiphenomenon of damaged or insufficient respiration.35 In many instances, tumorassociated mutations do not produce tumors when the tumor nucleus is placed in normal cytoplasm containing normal mitochondria.35,141 These observations also question the gene theory of cancer and the attempt to define the genetic nature of a disease that is not genetic.35

Role of Glucose and Glutamine in Brain Tumor Progression
Glucose is the predominant fuel of the brain, but also fuels tumor cell glycolysis as well as serving as a precursor for glutamate synthesis.50,70,79,80 Using linear regression analysis, we showed that the growth rate of an experimental mouse astrocytoma was directly dependent on blood glucose levels.79 The higher the blood glucose levels, the faster the tumors grew. As glucose levels fall, tumor size and growth rate falls. Hyperglycemia not only contributes to rapid tumor cell growth, but also enhances white matter damage in patients receiving radiation therapy.142 Hyperglycemia is also linked to poor prognosis in humans with malignant brain cancer.81,82

Moreover, we found that the expression of insulin-like growth factor 1 (IGF-1) was also dependent on circulating glucose levels.79,143 IGF-1 binds to IGF-1 receptor (IGF-1R), a cell surface receptor linked to rapid tumor growth through the PI3K/Akt signaling pathway.143 The association of plasma IGF-1 levels with tumor growth rate is due in part to elevated levels of blood glucose. These findings in animal models and in brain cancer patients indicate that tumor growth rate and prognosis is dependent to a significant extent on circulating glucose levels. Glucose is the prime fuel for glycolysis, which drives growth of most brain cancer.50,113,144 As long as circulating glucose levels remain elevated, brain tumor growth will be difficult to manage.

In addition to glucose, glutamine is also suggested to play an important role in tumor energy metabolism.145–148 In contrast to extracranial tissues where glutamine is the most available amino acid, glutamine is tightly regulated in the brain through its involvement in the glutamate– glutamine cycle of neurotransmission.70,149 Glutamate is a major excitatory neurotransmitter that must be cleared rapidly following synaptic release in order to prevent excitotoxic damage to neurons.55,149 Glial cells possess transporters for the clearance of extracellular glutamate, which is then metabolized to glutamine for delivery back to neurons. Neurons metabolize the glutamine to glutamate, which is then repackaged into synaptic vesicles for future release.149 The glutamate–glutamine cycle maintains low extracellular levels of both glutamate and glutamine in normal neural parenchyma. Disruption of the glutamate–glutamine cycle can cause neurotoxicity and provide neoplastic GBM cells access to glutamine as we recently described.51

Cytomegalovirus—An Oncomodulator of Brain Tumor Energy Metabolism
Many cancers including GBM are infected with HCMV, which acts as an oncomodulator of tumor progression.71,150,151 Products of the virus can damage mitochondria in the infected tumor cells thus contributing to a further dependence of these cells on glucose and glutamine for energy metabolism.72,152–154 The virus often infects cells of monocyte/ macrophage origin, which are considered the origin of many invasive and metastatic cancers, including GBM.22,86,155–157 Indeed, we proposed that neoplastic microglia/macrophages were the most invasive cells within GBM.22 GBM malignancy is correlated with the titer of HCMV infection. The higher the titer, the greater the malignancy.71 We suggest that HCMV infection in these neoplastic cells could contribute to the progression of GBM through an oncomodulatory effect on tumor cell energy metabolism.

Exploiting Mitochondrial Dysfunction for the Metabolic Management of Glioblastoma Multiforme—Role of Ketones and Ketogenic Diets
The high glycolytic rate and Warburg effect seen in GBM indicates that GBM, like most cancers, is primarily a disease of energy metabolism.36,47,50,54,113 Rational strategies for GBM management should therefore be found in therapies that can specifically target glycolytic tumor cell energy metabolism. As glucose is the major fuel for tumor energy metabolism through lactate fermentation, the restriction of glucose emerges as a rational therapeutic target for GBM management. However, most normal cells of the brain also need glycolytic pathway products, such as pyruvate, for energy production through OxPhos. It therefore becomes important to protect normal brain cells from drugs or therapies that disrupt glycolytic pathways or cause systemic reduction of glucose.

It is well known that ketones can replace glucose as an energy metabolite and can protect the brain from severe hypoglycemia.158–160 Ketone bodies (b-hydroxybutyrate [b-OHB] and acetoacetate) are generated almost exclusively in liver hepatocytes largely from fatty acids of triglyceride origin during periods of fasting.158,161,162 George Cahill considered ketones ‘good medicine’ for several neurologic and neurodegenerative diseases in patients with normal physiology.158,160,163–165 Ketone body metabolism reduces oxidative stress while enhancing metabolic efficiency of normal cells.161,166–168 In addition to providing an alternative fuel to glucose, b-OHB also acts as a histone deacetylase inhibitor, which could reduce glucose and glutamine metabolism.161 Tumor cells are unable to use ketone bodies for energy due to abnormalities in mitochondria structure or function.47,169–171 Moreover, our findings and those of others suggest that elevated ketones can be toxic to some tumor cells.35,172 A shift in energy metabolism associated with a low carbohydrate, high-fat ketogenic diet (KD) administered in restricted amounts (KD-R) will protect normal brain cells from glycolytic inhibition and the brain from hypoglycemia.

Nebeling and co-workers first showed that the KD was an effective nontoxic management for advanced stage astrocytoma in children.173 More recent studies in adult GBM patients support these early studies in children.174,175 It is important to mention that the therapeutic benefit for the KD is best when the diet is consumed in moderately restricted amounts rather than in unrestricted amounts. Restricted diets are those that deliver fewer total calories in order to lower circulating glucose and insulin levels. We showed in preclinical models of epilepsy and astrocytoma that blood glucose levels are lower while ketone levels are higher when the diet is consumed in restricted amounts than in unrestricted amounts.79,176,177

Humans, however, usually restrict intake of the KD due to the high fat content of the diet.178 Ketone bodies and fatty acids target appetite centers to reduce weight naturally.179 Moreover, prolonged unrestricted consumption of the KD can cause dyslipidemia, insulin resistance, and elevated glucose levels.180,181 It is also important to recognize that circulating ketone levels will rarely exceed 7–9 mmol in most patients without diabetes since excess ketones will be excreted in the urine.168 Ketoacidosis (above 15 mmol) is therefore not likely to occur in most GBM patients who would implement the KD-R. A moderate restriction of food intake in patients with GBM might reduce adverse effects even in the presence of steroids.174 It should also be recognized that the weight loss associated with dietary restriction is considered ‘healthy’ weight loss,182 whereas the weight loss associated with radiation and chemotherapy (fatigue, nausea, etc.) arises from the disease itself or from the toxic therapies used to treat the disease. Weight loss under these conditions is considered pathologic weight loss. This type of weight loss is in contrast to the mild weight loss associated with metabolic therapy, which will improve the overall health of the patient. The Longo group showed that water-only therapeutic fasting could improve the tolerance of patients to toxic cancer therapies.183 Hence, the KD-R can enhance general physiologic health while placing metabolic stress on tumor cells.

The metabolic shift from glucose metabolism to ketone body metabolism creates an anti-angiogenic, anti-inflammatory, and pro-apoptotic environment within the tumor microenvironment.59,79,169,184–186 There are no known drugs as effective in reducing angiogenesis and inflammation as calorie restriction.59,185 The general concept of a survival advantage of tumor cells over normal cells occurs when fermentable fuels are abundant, but not when they become limiting.35,187 Figure 4 illustrates the changes in whole body levels of blood glucose and ketone bodies (b-OHB) that are predicted to metabolically stress tumor cells while enhancing the metabolic efficiency of normal cells.188 This therapeutic strategy was illustrated previously in cancer patients and in preclinical models.167,173,175,177,189–191

In addition to lowering glucose availability to the tumor microenvironment, the KD-R could potentially lower brain glutamine levels thus restricting availability of this energy metabolite for tumor growth.192,193 The KD-R could be even more therapeutic if combined with non-toxic drugs that also target glycolysis, e.g., 2-deoxyglucose or 3-bromopyruvate.194,195 The KD-R could also further enhance GBM patient survival when combined with valganciclovir, which targets HCMV.196 HCMV infection of tumor cells contributes to elevated metabolism of glucose and glutamine.73,197 Recent evidence indicates that valganciclovir could significantly enhance survival of GBM patients.196 Further studies are needed to determine which combinations of drugs and treatments can act synergistically with the KD-R to target GBM energy metabolism.

Hyperbaric Oxygen Therapy Used in Conjunction with the Ketogenic Diet
Hyperbaric oxygen therapy (HBO2T) involves administration of 100 % oxygen at elevated pressure (greater than sea level, or 1 ATA). HBO2T increases plasma oxygen saturation and facilitates oxygen delivery to the tissue independent of hemoglobin O2 saturation.198,199 HBO2T has been used with radiotherapy to enhance brain tumor cell killing or to reduce brain tissue damage from the radiotherapy itself.11 HBO2T has not yet been used with the KD-R for brain cancer management. Poff et al. also recently showed a synergistic interaction between the KD and HBO2T for managing systemic metastatic cancer in mice (HBO2T).199 The KD reduces glucose for glycolytic energy, while also reducing NADPH levels for anti-oxidant potential through the pentose–phosphate pathway. HBO2T will increase reactive oxygen species (ROS) in the tumor cells while the ketones will protect normal cells against ROS damage and from the potential for central nervous system oxygen toxicity.161,169 Glucose deprivation will enhance oxidative stress in tumor cells, while increased oxygen can reduce tumor cell proliferation.200,201 In contrast to radiation therapy, which also kills tumor cells through ROS production,202 the KD + HBO2T will likely kill tumor cells without causing toxic collateral damage to normal cells.203 It will be interesting to determine if HBO2T + KD-R can be as effective as radiation therapy for managing malignant brain cancer.

According to the evidence presented here, the KD-R could provide a viable non-toxic option to the current SOC for managing malignant brain cancer. The potential efficacy of the KD-R could be enhanced further when combined with drugs and HBO2T, which create additional metabolic stress on tumor cells. The KD-R can target tumor cells globally without harming normal neurons and glia. The blood–brain barrier is less of a concern with the KD-R therapy than with conventional therapies. Although the KD-R therapy could be a more rational approach to malignant brain cancer management than is the current standard of cancer, the KD-R is not without some shortcomings. Compliance can be a major obstacle in attempting to implement the KD-R.47 Some people can have difficulty in maintaining blood glucose and ketones in the ranges needed to target angiogenesis and to control tumor growth and inflammation. Presently, considerable patient discipline and motivation is required for implementing the KD-R as a therapy. Many neurosurgeons and neurooncologists are also unfamiliar with the link between nutrition, tumor metabolism, tumor growth, and how the glycolytic phenotype of brain tumor cells can be exploited with metabolic therapy, either as an alternative approach or as an adjuvant to standard care. Consequently, some patients might be discouraged from using non-toxic strategies like the KD-R even when evidence suggests that dietary ketosis is safe and associated with improved outcome and quality of life. Nevertheless, we remain hopeful that the metabolic approach to brain cancer management using the KD-R together with synergistic drugs, HBO2T, and possibly a non-toxic antiviral therapy, will improve quality of life and longer-term survival for GBM patients. Neurooncologists should test this hypothesis.

Radiotherapy Used in Conjunction with the Ketogenic Diet
Despite the provocative effects of radiation on GBM growth and tumor cell survival, most GBM patients receive radiation as part of the SOC. Scheck and co-workers reported that radiation therapy against glioma growth in mice could be enhanced when combined with the KD.204 Klement and Champ recently described how calorie restriction and the KD could reduce the adverse effects of radiation therapy to enhance overall therapeutic efficacy for cancer management.175,205,206 It will be important to determine if radiation therapy can eventually be replaced with more effective and less toxic therapies. Until such time, it might be best to administer radiation therapy together with the KD-R or with another form of metabolic therapy that can lower blood glucose and elevate ketones.

Conclusions
As long as brain cancer is viewed as something other than a metabolic disease, it is unlikely that major progress will be realized in improving survival.49 The current SOC for GBM offers little hope of improved quality of life or long-term patient survival.89 If GBM becomes viewed as a metabolic disease, however, we might anticipate major advances in treatment and substantial improvement in quality of life and overall survival. Metabolic therapy will target the abnormalities in tumor cell energy metabolism without damaging normal brain tissue or producing adverse systemic effects. We think it is possible that non-toxic therapies could eventually replace toxic therapies for GBM management. Unfortunately, there is a critical lack of clinical trials in using metabolic therapy for GBM management as an alternative to the current treatments. In this vision of personalized metabolic medicine, clinical personnel specialized in metabolism, endocrinology, and nutrition will become part of neurooncology teams to enroll patients who refuse aggressive chemotherapy treatments in phase I\II clinical trials using the KD-R + HBO2T. The application of metabolic therapy for brain cancer management is gaining momentum, but progress has been slow.207 We remain hopeful that the metabolic approach to brain cancer management using the KD-R together with synergistic drugs and HBO2T will offer the best chance for improved patient outcome. Metabolic therapy could become the new SOC if the impressive results in preclinical studies and in human case reports can be replicated in larger patient populations.

Article Information:
Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Thomas N Seyfried, PhD, Professor of Biology, Biology Department, Boston College, Chestnut Hill, MA 02467, US. E: Thomas.seyfried@bc.edu

An erratum to this article can be found below.

Received

2014-02-09T00:00:00

References

  1. Patil CG, Yi A, Elramsisy A, et al., Prognosis of patients with multifocal glioblastoma: a case-control study, J Neurosurg, 2012;117:705–11.
  2. Fisher PG, Buffler PA, Malignant gliomas in 2005: where to GO from here?, JAMA, 2005;293:615–7.
  3. Stupp R, Hegi ME, Mason WP, et al., Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial, Lancet Oncol, 2009;10:459–66.
  4. Krex D, Klink B, Hartmann C, et al., Long-term survival with glioblastoma multiforme, Brain, 2007;130:2596–606.
  5. Karsy M, Gelbman M, Shah P, et al., Established and emerging variants of glioblastoma multiforme: review of morphological and molecular features, Folia Neuropathol, 2012;50:301–21.
  6. Chen R, Nishimura MC, Bumbaca SM, et al., A hierarchy of selfrenewing tumor-initiating cell types in glioblastoma, Cancer Cell, 2010;17:362–75.
  7. Ohgaki H, Kleihues P, Genetic alterations and signaling pathways in the evolution of gliomas, Cancer Sci, 2009;100:2235–41.
  8. Prestegarden L, Svendsen A, Wang J, et al., Glioma cell populations grouped by different cell type markers drive brain tumor growth, Cancer Res, 2010;70:4274–9.
  9. Tso CL, Shintaku P, Chen J, et al., Primary glioblastomas express mesenchymal stem-like properties. Mol Cancer Res, 2006;4:607–19.
  10. Rubinstein LJ, Tumors of the central nervous system, Washington, DC, Armed Forces Institute of Pathology, 1972.
  11. Kohshi K, Beppu T, Tanaka K, et al., Potential roles of hyperbaric oxygenation in the treatments of brain tumors, UHM, 2013;40:351–62.
  12. Lopes MBS, Vanbenberg SR, Scheithauer BW, The World Health Organization classification of nervous system tumors in experimental neuro-oncology. In: Levine AJ, Schmidek HH, (editors), Molecular Genetics of Nervous System Tumors, New York: John Wiley & Sons, 1993;1–36.
  13. Johnson BE, Mazor T, Hong C, et al., Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma, Science, 2014;343:189–93.
  14. Sanai N, Chang S, Berger MS, Low-grade gliomas in adults, J Neurosurg, 2011;115:948–65.
  15. Shinonaga M, Chang CC, Suzuki N, et al., Immunohistological evaluation of macrophage infiltrates in brain tumors. Correlation with peritumoral edema, J Neurosurg, 1988;68:259–65.
  16. Nishie A, Ono M, Shono T, et al., Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas, Clin Cancer Res, 1999;5:1107–13.
  17. Phillips JP, Eremin O, Anderson JR, Lymphoreticular cells in human brain tumours and in normal brain, Br J Cancer, 1982;45:61–9.
  18. Seyfried TN, Shelton LM, Mukherjee P, Does the existing standard of care increase glioblastoma energy metabolism?, Lancet Oncol, 2010;11:811–3.
  19. Morantz RA, Wood GW, Foster M, et al., Macrophages in experimental and human brain tumors. Part 2: studies of the macrophage content of human brain tumors, J Neurosurg, 1979;50:305–11.
  20. Seyfried TN, Perspectives on brain tumor formation involving macrophages, glia, and neural stem cells, Perspect Biol Med, 2001;44:263–82.
  21. Lewis C, Murdoch C, Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies, Am J Pathol, 2005;167:627–35.
  22. Huysentruyt LC, Akgoc Z, Seyfried TN, Hypothesis: are neoplastic macrophages/microglia present in glioblastoma23. Talacchi A, Turazzi S, Locatelli F, et al., Surgical treatment of high-grade gliomas in motor areas. The impact of different supportive technologies: a 171-patient series, J Neurooncol, 2010;100:417–26.
  23. Kallenberg K, Bock HC, Helms G, et al., Untreated glioblastoma multiforme: increased myo-inositol and glutamine levels in the contralateral cerebral hemisphere at proton MR spectroscopy, Radiology, 2009;253:805–12.
  24. Zagzag D, Esencay M, Mendez O, et al., Hypoxia- and vascular endothelial growth factor-induced stromal cell-derived factor-1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Scherer’s structures, Am J Pathol, 2008;173:545–60.
  25. Scherer HJ, Structural Development in gliomas, Am J Cancer, 1938;34.
  26. Liwnicz BH, Rubinstein LJ, The pathways of extraneural spread in metastasizing gliomas: a report of three cases and critical review of the literature, Hum Pathol, 1979;10:453–67.
  27. Kalokhe G, Grimm SA, Chandler JP, et al., Metastatic glioblastoma: case presentations and a review of the literature, J Neurooncol, 2012;107:21–7.
  28. Beauchesne P, Extra-neural metastases of malignant gliomas: myth or reality?, Cancers (Basel), 2011;3:461–77.
  29. Armanios MY, Grossman SA, Yang SC, et al., Transmission of glioblastoma multiforme following bilateral lung transplantation from an affected donor: case study and review of the literature, Neuro-oncology, 2004;6:259–63.
  30. Lun M, Lok E, Gautam S, et al., The natural history of extracranial metastasis from glioblastoma multiforme, J Neurooncol, 2011;105:261–73.
  31. Parsons DW, Jones S, Zhang X, et al., An integrated genomic analysis of human glioblastoma multiforme, Science, 2008;321:1807–12.
  32. Brennan CW, Verhaak RG, McKenna A, et al., The somatic genomic landscape of glioblastoma, Cell, 2013;155:462–77.
  33. Holdhoff M, Ye X, Blakeley JO, et al., Use of personalized molecular biomarkers in the clinical care of adults with glioblastomas, J Neurooncol, 2012;110:279–85.
  34. Seyfried TN, Flores RE, Poff AM, D’Agostino DP, Cancer as a metabolic disease: implications for novel therapeutics, Carcinogenesis, 2014;35:515–27.
  35. Seyfried TN, Cancer as a metabolic disease: on the origin, management, and prevention of cancer, Hoboken, NJ: John Wiley & Sons, 2012.
  36. Mrugala MM, Advances and challenges in the treatment of glioblastoma: a clinician’s perspective, Discov Med, 2013;15:221–30.
  37. Mason WP, Maestro RD, Eisenstat D, et al., Canadian recommendations for the treatment of glioblastoma multiforme, Curr Oncol, 2007;14:110–7.
  38. Koehler PJ, Use of corticosteroids in neuro-oncology, Anticancer Drugs, 1995;6:19–33.
  39. Chang SM, Parney IF, Huang W, et al., Patterns of care for adults with newly diagnosed malignant glioma, JAMA, 2005;293:557–64.
  40. Souhami L, Seiferheld W, Brachman D, et al., Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol, Int J Radiat Oncol Biol Phys, 2004;60:853–60.
  41. Yin AA, Cheng JX, Zhang X, Liu BL, The treatment of glioblastomas: a systematic update on clinical Phase III trials, Crit Rev Oncol Hematol, 2013;87:265–82.
  42. Yin AA, Zhang LH, Cheng JX, et al., Radiotherapy plus concurrent or sequential temozolomide for glioblastoma in the elderly: a meta-analysis, PLoS One, 2013;8:e74242.
  43. Davis FG, Freels S, Grutsch J, et al., Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973–1991, J Neurosurg, 1998;88:1–10.
  44. Stupp R, Mason WP, van den Bent MJ, et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N Engl J Med, 2005;352:987–96.
  45. Burton TM, Dooren JC, Key FDA approval yanked for avastin, Wall Street Journal, November 19, 2011.
  46. Seyfried TN, Marsh J, Shelton LM, et al., Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?, Epilepsy Res, 2012;100:310–26.
  47. Seyfried TN, Cancer treatment strategies. In: Cancer as a metabolic disease: on the origin, management, and prevention of cancer, Hoboken, NJ: John Wiley & Sons, 2012;227–89.
  48. Han K, Ren M, Wick W, et al., Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials, Neuro-oncology, 2014 [Epub ahead of print].
  49. Seyfried TN, Mukherjee P, Targeting energy metabolism in brain cancer: review and hypothesis, Nutr Metab (Lond), 2005;2:30.
  50. Seyfried TN, Kiebish MA, Marsh J, et al., Metabolic management of brain cancer, Biochim Biophys Acta, 2010;1807:577–94.
  51. Yang C, Sudderth J, Dang T, et al., Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling, Cancer Res, 2009;69:7986–93.
  52. Dang CV, Glutaminolysis: supplying carbon or nitrogen or both for cancer cells?, Cell Cycle, 2010;9:3884–6.
  53. Seyfried TN, Mukherjee P, Kalamian M, Zuccoli G, The restricted ketogenic diet: An alternative treatment strategy for glioblastoma multiforme. In: Holcroft R, editor, Treatment Strategies Oncology, London: Cambridge Research Centre, 2011;24–35.
  54. Takano T, Lin JH, Arcuino G, et al., Glutamate release promotes growth of malignant gliomas, Nat Med, 2001;7:1010–5.
  55. Monje ML, Vogel H, Masek M, et al., Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies, Ann Neurol, 2007;62:515–20.
  56. Lee WH, Sonntag WE, Mitschelen M, et al., Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain, Int J Radiat Biol, 2010;86:132–44.
  57. Di Chiro G, Oldfield E, Wright DC, et al., Cerebral necrosis after radiotherapy and/or intraarterial chemotherapy for brain tumors: PET and neuropathologic studies, AJR Am J Roentgenol, 1988;150:189–97.
  58. Mukherjee P, El-Abbadi MM, Kasperzyk JL, et al., Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model, Br J Cancer, 2002;86:1615–21.
  59. Shah R, Vattoth S, Jacob R, et al., Radiation necrosis in the brain: imaging features and differentiation from tumor recurrence, Radiographics, 2012;32:1343–59.
  60. Zhou J, Tryggestad E, Wen Z, et al., Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides, Nat Med, 2011;17:130–4.
  61. Xu RH, Pelicano H, Zhou Y, et al., Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia, Cancer Res, 2005;65:613–21.
  62. Elstrom RL, Bauer DE, Buzzai M, et al., Akt stimulates aerobic glycolysis in cancer cells, Cancer Res, 2004;64:3892–9.
  63. Kargiotis O, Geka A, Rao JS, Kyritsis AP, Effects of irradiation on tumor cell survival, invasion and angiogenesis, J Neurooncol, 2010;100:323–38.
  64. Zhuang W, Qin Z, Liang Z, The role of autophagy in sensitizing malignant glioma cells to radiation therapy, Acta Biochim Biophys Sin (Shanghai), 2009;41:341–51.
  65. Seyfried TN, Shelton LM, Cancer as a metabolic disease, Nutr Metab (Lond), 2010;7:7.
  66. Taphoorn MJ, Stupp R, Coens C, et al., Health-related quality of life in patients with glioblastoma: a randomised controlled trial, Lancet Oncol, 2005;6:937–44.
  67. Liu R, Solheim K, Polley MY, et al., Quality of life in low-grade glioma patients receiving temozolomide, Neuro-oncology, 2009;11:59–68.
  68. Bower JE, Ganz PA, Irwin MR, et al., Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism?, J Clin Oncol, 2011;29:3517–22.
  69. McKenna MC, Gruetter R, Sonnewald U, et al., Energy metabolism of the brain. In: Siegel GJ, Albers RW, Bradey ST, Price DP, editors, Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, New York: Elsevier Academic Press, 2006;531–57.
  70. Dziurzynski K, Chang SM, Heimberger AB, et al., Consensus on the role of human cytomegalovirus in glioblastoma, Neurooncology, 2012;14:246–55.
  71. Yu Y, Clippinger AJ, Alwine JC, Viral effects on metabolism: changes in glucose and glutamine utilization during human cytomegalovirus infection, Trends Microbiol, 2011;19:360–7.
  72. Lawrence YR, Wang M, Dicker AP, et al., Early toxicity predicts long-term survival in high-grade glioma, Br J Cancer, 2011;104:1365–71.
  73. Harris D, Barts A, Connors J, et al., Glucocorticoid-induced hyperglycemia is prevalent and unpredictable for patients undergoing cancer therapy: an observational cohort study, Curr Oncol, 2013;20:e532–8.
  74. Noch E, Khalili K, Molecular mechanisms of necrosis in glioblastoma: the role of glutamate excitotoxicity, Cancer Biol Ther, 2009;8:1791–7.
  75. Lukins MB, Manninen PH, Hyperglycemia in patients administered dexamethasone for craniotomy, Anesth Analg, 2005;100:1129–33.
  76. Hans P, Vanthuyne A, Dewandre PY, et al., Blood glucose concentration profile after 10 mg dexamethasone in nondiabetic and type 2 diabetic patients undergoing abdominal surgery, Br J Anaesth, 2006;97:164–70.
  77. Hockey B, Leslie K, Williams D, Dexamethasone for intracranial neurosurgery and anaesthesia, J Clin Neurosci, 2009;16:1389–93.
  78. Seyfried TN, Sanderson TM, El-Abbadi MM, et al., Role of glucose and ketone bodies in the metabolic control of experimental brain cancer, Br J Cancer, 2003;89:1375–82.
  79. Warburg O, On the origin of cancer cells, Science, 1956;123:309–14.
  80. McGirt MJ, Chaichana KL, Gathinji M, et al., Persistent outpatient hyperglycemia is independently associated with decreased survival after primary resection of malignant brain astrocytomas, Neurosurgery, 2008;63:286–91; discussion 91.
  81. Derr RL, Ye X, Islas MU, et al., Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma, J Clin Oncol, 2009;27:1082–6.
  82. Reardon DA, Desjardins A, Peters K, et al., Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy, J Neurooncol, 2011;103:371–9.
  83. Iwamoto FM, Abrey LE, Beal K, et al., Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma, Neurology, 2009;73:1200–6.
  84. de Groot JF, Fuller G, Kumar AJ, et al., Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice, Neuro-oncology, 2010;12:233–42.
  85. Seyfried TN, Huysentruyt LC, On the origin of cancer metastasis, Crit Rev Oncog, 2013;18:43–73.
  86. Jeyaretna DS, Curry WT, Jr, Batchelor TT, et al., Exacerbation of cerebral radiation necrosis by bevacizumab, J Clin Oncol, 2011;29:e159–62.
  87. Lawrence YR, Mishra MV, Werner-Wasik M, et al., Improving prognosis of glioblastoma in the 21st century: who has benefited most?, Cancer, 2012;118:4228–34.
  88. Stratton MR, Exploring the genomes of cancer cells: progress and promise, Science, 2011;331:1553–8.
  89. Stratton MR, Campbell PJ, Futreal PA, The cancer genome, Nature, 2009;458:719–24.
  90. Schwartzentruber J, Korshunov A, Liu XY, et al., Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma, Nature, 2012;482:226–31.
  91. Pedersen PL, Tumor mitochondria and the bioenergetics of cancer cells, Prog Exp Tumor Res, 1978;22:190–274.
  92. Arismendi-Morillo GJ, Castellano-Ramirez AV, Ultrastructural mitochondrial pathology in human astrocytic tumors: potentials implications pro-therapeutics strategies, J Electron Microsc (Tokyo), 2008;57:33–9.
  93. Ordys BB, Launay S, Deighton RF, et al., The role of mitochondria in glioma pathophysiology, Mol Neurobiol, 2010;42:64–75.
  94. Hanahan D, Weinberg RA, Hallmarks of cancer: the next generation, Cell, 2011;144:646–74.
  95. John AP, Dysfunctional mitochondria, not oxygen insufficiency, cause cancer cells to produce inordinate amounts of lactic acid: the impact of this on the treatment of cancer, Med Hypotheses, 2001;57:429–31.
  96. Roskelley RC, Mayer N, Horwitt BN, Salter WT, Studies in cancer. VII. Enzyme deficiency in human and experimental cancer, J Clin Invest, 1943;22:743–51.
  97. Arismendi-Morillo G, Electron microscopy morphology of the mitochondrial network in human cancer, Int J Biochem Cell Biol, 2009;41:2062–8.
  98. Carew JS, Huang P, Mitochondrial defects in cancer, Mol Cancer, 2002;1:9.
  99. Villalobo A, Lehninger AL, The proton stoichiometry of electron transport in Ehrlich ascites tumor mitochondria, Biol Chem, 1979;254:4352–8.
  100. Ramanathan A, Wang C, Schreiber SL, Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements, Proc Natl Acad Sci U S A, 2005;102:5992–7.
  101. Cuezva JM, Krajewska M, de Heredia ML, et al., The bioenergetic signature of cancer: a marker of tumor progression, Cancer Res, 2002;62:6674–81.
  102. Bayley JP, Devilee P, Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree?, Curr Opin Genet Dev, 2010;20:324–9.
  103. Arismendi-Morillo G, Electron microscopy morphology of the mitochondrial network in gliomas and their vascular microenvironment, Biochim Biophys Acta, 2011;1807:602–8.
  104. Cogliati S, Frezza C, Soriano ME, et al., Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency, Cell, 2013;155:160–71.
  105. Stroud DA, Ryan MT, Mitochondria: organization of respiratory chain complexes becomes cristae-lized, Curr Biol, 2013;23:R969–71.
  106. Galluzzi L, Morselli E, Kepp O, et al., Mitochondrial gateways to cancer, Mol Aspects Med, 2010;31:1–20.
  107. Kiebish MA, Han X, Cheng H, Seyfried TN, In vitro growth environment produces lipidomic and electron transport chain abnormalities in mitochondria from non-tumorigenic astrocytes and brain tumours, ASN Neuro, 2009;1:e00011.
  108. Kiebish MA, Han X, Cheng H, et al., Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer, J Lipid Res, 2008;49:2545–56.
  109. Chicco AJ, Sparagna GC, Role of cardiolipin alterations in mitochondrial dysfunction and disease, Am J Physiol Cell Physiol, 2007;292:C33–44.
  110. Fry M, Green DE, Cardiolipin requirement for electron transfer in complex I and III of the mitochondrial respiratory chain, J Biol Chem, 1981;256:1874–80.
  111. Claypool SM, Koehler CM, The complexity of cardiolipin in health and disease, Trends Biochem Sci, 2012;37:32–41.
  112. Oudard S, Boitier E, Miccoli L, et al., Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultrastructure, Anticancer Res, 1997;17:1903–11.
  113. Warburg O, The Metabolism of Tumours, New York: Richard R. Smith, 1931.
  114. Zu XL, Guppy M, Cancer metabolism: facts, fantasy, and fiction, Biochem Biophys Res Commun, 2004;313:459–65.
  115. Koppenol WH, Bounds PL, Dang CV, Otto Warburg’s contributions to current concepts of cancer metabolism,117. Cuezva JM, Chen G, Alonso AM, et al., The bioenergetic signature of lung adenocarcinomas is a molecular marker of cancer diagnosis and prognosis, Carcinogenesis, 2004;25:1157–63.
  116. Ferreira LM, Cancer metabolism: the Warburg effect today, Exp Mol Pathol, 2010;89:372–80.
  117. Seyfried TN, The Warburg dispute. In: Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer, 2012:107–17.
  118. Gonzalez MJ, Miranda Massari JR, Duconge J, et al., The bio-energetic theory of carcinogenesis, Med Hypotheses, 2012;79:43–9.
  119. Dakubo GD, The Warburg phenomenon and other metabolic alterations of cancer cells. In: Mitochondrial Genetics and Cancer. New York: Springer, 2010;39–66.
  120. Pedersen PL, Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the ‘Warburg Effect’, i.e., elevated glycolysis in the presence of oxygen, J Bioenerg Biomembr, 2007;39:211–22.
  121. Warburg O, On the respiratory impairment in cancer cells, Science (New York, NY), 1956;124:269–70.
  122. Warburg O, Revidsed Lindau Lectures: The prime cause of cancer and prevention – Parts 1 & 2. In: Burk D, editor, Meeting of the Nobel-Laureates Lindau, Lake Constance, Germany: K Triltsch, 1969.
  123. Seyfried TN, Respiratory dysfunction in cancer cells. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer, Hoboken, NJ: John Wiley & Sons, 2012:73–105.
  124. Lichtor T, Dohrmann GJ, Respiratory patterns in human brain tumors, Neurosurgery, 1986;19:896–9.
  125. Shelton LM, Strelko CL, Roberts MF, Seyfried NT, Krebs cycle substrate-level phosphorylation drives metastatic cancer cells. Proceedings of the 101st Annual Meeting of the American Association for Cancer Research, Washington, DC, 2010.
  126. Seyfried TN, Mitochondrial glutamine fermentation enhances ATP synthesis in murine glioblastoma cells. Proceedings of the 102nd Annual Meeting of the Amer Assoc Cancer Res, Orlando, FL, 2011.
  127. Seyfried TN, Is mitochondrial glutamine fermentation a missing link in the metabolic theory of cancer? In: Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer, Hoboken, NJ: John Wiley & Sons; 2012;133–44.
  128. Chinopoulos C, Gerencser AA, Mandi M, et al., Forward operation of adenine nucleotide translocase during F0F1- ATPase reversal: critical role of matrix substrate-level phosphorylation, Faseb J, 2010;24:2405–16.
  129. Phillips D, Aponte AM, French SA, et al., Succinyl-CoA synthetase is a phosphate target for the activation of mitochondrial metabolism, Biochemistry, 2009;48:7140–9.
  130. Schwimmer C, Lefebvre-Legendre L, Rak M, et al., Increasing mitochondrial substrate-level phosphorylation can rescue respiratory growth of an ATP synthase-deficient yeast, J Biol Chem, 2005;280:30751–9.
  131. Lu J, Sharma LK, Bai Y, Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis, Cell research, 2009;19:802–15.
  132. Yang D, Wang MT, Tang Y, et al., Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-RAS(Q61L), Cancer Biol Ther, 2010;9:122–33.
  133. Smiraglia DJ, Kulawiec M, Bistulfi GL, et al., A novel role for mitochondria in regulating epigenetic modification in the nucleus, Cancer Biol Ther, 2008;7:1182–90.
  134. Delsite RL, Rasmussen LJ, Rasmussen AK, et al., Mitochondrial impairment is accompanied by impaired oxidative DNA repair in the nucleus, Mutagenesis, 2003;18:497–503.
  135. Kulawiec M, Safina A, Desouki MM, et al., Tumorigenic transformation of human breast epithelial cells induced by mitochondrial DNA depletion, Cancer Biol Ther, 2008;7.
  136. Rasmussen AK, Chatterjee A, Rasmussen LJ, Singh KK, Mitochondria-mediated nuclear mutator phenotype in Saccharomyces cerevisiae, Nucleic Acids Res, 2003;31:3909–17.
  137. Chandra D, Singh KK, Genetic insights into OXPHOS defect and its role in cancer, Biochim Biophys Acta, 2011;1807:620–5.
  138. Veatch JR, McMurray MA, Nelson ZW, Gottschling DE, Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur cluster defect, Cell, 2009;137:1247–58.
  139. Seyfried TN, Mitochondria: The ultimate tumor suppressor. In: Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer, Hoboken, NJ: John Wiley & Sons, 2012;195–205.
  140. Szerlip N, Rutter C, Ram N, et al., Factors impacting volumetric white matter changes following whole brain radiation therapy, J Neurooncol, 2011;103:111–9.
  141. Marsh J, Mukherjee P, Seyfried TN, Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma, Clin Cancer Res, 2008;14:7751–62.
  142. Oudard S, Arvelo F, Miccoli L, et al., High glycolysis in gliomas despite low hexokinase transcription and activity correlated to chromosome 10 loss, Br J Cancer, 1996;74:839–45.
  143. DeBerardinis RJ, Cheng T, Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer, Oncogene, 2010;29:313–24.
  144. Gao P, Tchernyshyov I, Chang TC, et al., c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism, Nature, 2009;458:762–5.
  145. Wise DR, DeBerardinis RJ, Mancuso A, et al., Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proc Natl Acad Sci U S A, 2008;105:18782–7.
  146. Yuneva M, Finding an ‘Achilles’ heel’ of cancer: the role of glucose and glutamine metabolism in the survival of transformed cells, Cell Cycle, 2008;7:2083–9.
  147. Hawkins RA, The blood-brain barrier and glutamate, Am J Clin Nutr, 2009;90:867S–74S.
  148. Hawkins C, Croul S, Viruses and human brain tumors: cytomegalovirus enters the fray, J Clin Invest, 2011;121:3831–3.
  149. Michaelis M, Doerr HW, Cinatl J, The story of human cytomegalovirus and cancer: increasing evidence and open questions, Neoplasia, 2009;11:1–9.
  150. Bozidis P, Williamson CD, Wong DS, Colberg-Poley AM, Trafficking of UL37 proteins into mitochondrion-associated membranes during permissive human cytomegalovirus infection, J Virol, 2010;84:7898–903.
  151. Williamson CD, Colberg-Poley AM, Access of viral proteins to mitochondria via mitochondria-associated membranes, Rev Med Virol, 2009;19:147–64.
  152. Seyfried TN, Genes, respiration, viruses, and cancer. In: Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer, Hoboken, NJ: John Wiley & Sons, 2012;145–76.
  153. Pawelek JM, Chakraborty AK, The cancer cell–leukocyte fusion theory of metastasis, Adv Cancer Res, 2008;101:397-444.
  154. Dziurzynski K, Wei J, Qiao W, et al., Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype, Clin Cancer Res, 2011;17:4642–9.
  155. Munzarova M, Rejthar A, Mechl Z, Do some malignant melanoma cells share antigens with the myeloid monocyte lineage?, Neoplasma, 1991;38:401–5.
  156. VanItallie TB, Nufert TH, Ketones: metabolism’s ugly duckling, Nutr Rev, 2003;61:327–41.
  157. Drenick EJ, Alvarez LC, Tamasi GC, Brickman AS, Resistance to symptomatic insulin reactions after fasting, J Clin Invest, 1972;51:2757–62.
  158. Veech RL, The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism, Prostaglandins Leukot Essent Fatty Acids, 2004;70:309–19.
  159. Newman JC, Verdin E, Ketone bodies as signaling metabolites, Trends Endocrinol Metab, 2014;25:42–52.
  160. Krebs HA, Williamson DH, Bates MW, et al., The role of ketone bodies in caloric homeostasis, Adv Enzyme Reg, 1971;9:387–409.
  161. Freeman JM, Kossoff EH, Ketosis and the ketogenic diet, 2010: advances in treating epilepsy and other disorders, Adv Pediatr, 2010;57:315–29.
  162. Cahill GF, Jr, Veech RL, Ketoacids? Good medicine? Trans Am Clin Climatol Assoc, 2003;114:149–61; discussion 62–3.
  163. Maalouf M, Rho JM, Mattson MP, The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies, Brain Res Rev, 2009;59:293–315.
  164. Milder J, Patel M, Modulation of oxidative stress and mitochondrial function by the ketogenic diet, Epilepsy Res, 2012;100:295–303.
  165. Stafford P, Abdelwahab MG, Kim do Y, et al., The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma, Nutr Metab (Lond), 2010;7:74.
  166. Veech RL, Chance B, Kashiwaya Y, et al., Ketone bodies, potential therapeutic uses, IUBMB Life, 2001;51:241–7.
  167. Seyfried TN, Metabolic management of cancer. In: Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer, Hoboken, NJ: John Wiley & Sons, 2012;291–354.
  168. Fredericks M, Ramsey RB, 3-Oxo acid coenzyme A transferase activity in brain and tumors of the nervous system, J Neurochem, 1978;31:1529–31.
  169. Maurer GD, Brucker DP, Baehr O, et al., Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy, BMC Cancer, 2011;11:315.
  170. Skinner R, Trujillo A, Ma X, Beierle EA, Ketone bodies inhibit the viability of human neuroblastoma cells, J Pediatr Surg, 2009;44:212–6, discussion 6.
  171. Nebeling LC, Miraldi F, Shurin SB, Lerner E, Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports, J Am Coll Nutr, 1995;14:202–8.
  172. Champ CE, Palmer JD, Volek JS, et al., Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme, J Neurooncol, 2014;117:125–31.
  173. Zuccoli G, Marcello N, Pisanello A, et al., Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report, Nutr Metab (Lond), 2010;7:33.
  174. Mantis JG, Centeno NA, Todorova MT, Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the ketogenic diet: role of glucose and ketone bodies, Nutr Metab (Lond), 2004;1:11.
  175. Zhou W, Mukherjee P, Kiebish MA, et al., The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer, Nutr Metab (Lond), 2007;4:5.
  176. Johnstone AM, Horgan GW, Murison SD, et al., Effects of a highprotein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum, Am J Clin Nutr, 2008;87:44–55.
  177. Le Foll C, Dunn-Meynell AA, Miziorko HM, Levin BE, Regulation of hypothalamic neuronal sensing and food intake by ketone bodies and fatty acids, Diabetes, 2014;63:1259–69.
  178. Borghjid S, Feinman RD, Response of C57Bl/6 mice to a carbohydrate-free diet, Nutr Metab (Lond), 2012;9:69.
  179. Ellenbroek JH, van Dijck L, Tons HA, et al., Long-term ketogenic diet causes glucose intolerance and reduced beta and alpha cell mass but no weight loss in mice, Am J Physiol Endocrinol Metab, 2014;306:E552–8.
  180. Paoli A, Rubini A, Volek JS, Grimaldi KA, Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets, Eur J Clin Nutr, 2013;67:789–96.
  181. Raffaghello L, Safdie F, Bianchi G, et al., Fasting and differential chemotherapy protection in patients, Cell Cycle, 2010;9:4474–6.
  182. Jiang YS, Wang FR, Caloric restriction reduces edema and prolongs survival in a mouse glioma model, J Neurooncol, 2013;114:25–32.
  183. Mukherjee P, Abate LE, Seyfried TN, Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors, Clin Cancer Res, 2004;10:5622–9.
  184. Mulrooney TJ, Marsh J, Urits I, et al., Influence of Caloric Restriction on Constitutive Expression of NF-kappaB in an Experimental Mouse Astrocytoma, PloS One, 2011;6:e18085.
  185. Seyfried TN, Nothing in cancer biology makes sense except in the light of evolution. In: Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer, Hoboken, NJ, John Wiley & Sons, 2012:261–75.
  186. Seyfried TN, Kiebish M, Mukherjee P, Marsh J, Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets, Epilepsia, 2008;49(Suppl. 8):114–6.
  187. Simone BA, Champ CE, Rosenberg AL, et al., Selectively starving cancer cells through dietary manipulation: methods and clinical implications, Future Oncol, 2013;9:959–76.
  188. Fine EJ, Segal-Isaacson CJ, Feinman RD, et al., Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients, Nutrition, 2012;28:1028–35.
  189. Urits I, Mukherjee P, Meidenbauer J, Seyfried TN, Dietary restriction promotes vessel maturation in a mouse astrocytoma, J Oncology, 2012;2012:264039.
  190. Kashiwaya Y, Pawlosky R, Markis W, et al., A ketone ester diet increased brain malonyl CoA and uncoupling protein 4 and 5 while decreasing food intake in the normal Wistar rat, J Biol Chem, 2010;285:25950–6.
  191. Yudkoff M, Daikhin Y, Melo TM, et al., The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect, Annu Rev Nutr, 2007;27:415–30.
  192. Ko YH, Smith BL, Wang Y, et al., Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP, Biochem Biophys Res Commun, 2004;324:269–75.
  193. Marsh J, Mukherjee P, Seyfried TN, Drug/diet synergy for managing malignant astrocytoma in mice: 2-deoxy-D-glucose and the restricted ketogenic diet, Nutr Metab (Lond), 2008;5:33.
  194. Soderberg-Naucler C, Rahbar A, Stragliotto G, Survival in patients with glioblastoma receiving valganciclovir, N Engl J Med, 2013;369:985–6.
  195. Yu Y, Maguire TG, Alwine JC, Human cytomegalovirus activates glucose transporter 4 expression to increase glucose uptake during infection, J Virol, 2011;85:1573–80.
  196. Gill AL, Bell CN, Hyperbaric oxygen: its uses, mechanisms of action and outcomes, QJM, 2004;97:385–95.
  197. Poff AM, Ari C, Seyfried TN, D’Agostino DP, The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer, PloS One, 2013;8:e65522.
  198. Chen Y, Cairns R, Papandreou I, et al., Oxygen consumption can regulate the growth of tumors, a new perspective on the warburg effect, PloS One, 2009;4:e7033.
  199. Spitz DR, Sim JE, Ridnour LA, et al., Glucose deprivationinduced oxidative stress in human tumor cells. A fundamental defect in metabolism?, Ann N Y Acad Sci, 2000;899:349–62.
  200. Harrison L, Blackwell K, Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? Oncologist, 2004;9(Suppl. 5):31–40.
  201. D’Agostino DP, Olson JE, Dean JB, Acute hyperoxia increases lipid peroxidation and induces plasma membrane blebbing in human U87 glioblastoma cells, Neuroscience, 2009;159:1011–22.
  202. Abdelwahab MG, Fenton KE, Preul MC, et al., The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma, PloS One, 2012;7:e36197.
  203. Klement RJ, Calorie or carbohydrate restriction? The ketogenic diet as another option for supportive cancer treatment, Oncologist, 2013;18:1056.
  204. Klement RJ, Champ CE, Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation, Cancer Metastasis Rev, 2014 [Epub ahead of print].
  205. Maroon J, Bost J, Amos A, Zuccoli G, Restricted calorie ketogenic diet for the treatment of glioblastoma multiforme, J Child Neurol, 2013;28:1002–8.

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