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

Oncology & Hematology Review, 2014;10(1):13–20


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
Disclosure: The authors have no conflicts of interest to declare.
Acknowledgments: This research was supported in part by National Institutes of Health (NIH) grants (HD-39722, NS-55195, and CA-102135), a grant from the American Institute of Cancer, the Boston College Expense Fund (to Thomas N Seyfried, PhD), Scivation, and the Office of Naval Research (to Dominic P D’Agostino, PhD).
Received: February 09, 2014 Accepted March 05, 2014 Citation Oncology & Hematology Review, 2014;10(1):13–20
Correspondence: Thomas N Seyfried, PhD, Professor of Biology, Biology Department, Boston College, Chestnut Hill, MA 02467, US. E:

An erratum to this article can be found below.

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.

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