Metabolic therapy: A new paradigm for managing malignant brain cancer

Cancer Letters xxx (2014) xxx–xxx

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Cancer Letters

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Mini-review

Metabolic therapy: A new paradigm for managing malignant braincancer

http://dx.doi.org/10.1016/j.canlet.2014.07.0150304-3835/� 2014 Published by Elsevier Ireland Ltd.

Abbreviations: KD-R, calorically restricted ketogenic diet; OxPhos, oxidativephosphorylation; HCMV, human cytomegalovirus.⇑ Corresponding author. Address: Biology Department, Boston College, Chestnut

Hill, MA 0246, USA. Tel.: +1 617 552 3563; fax: +1 617 552 2011.E-mail address: [email protected] (T.N. Seyfried).

Please cite this article in press as: T.N. Seyfried et al., Metabolic therapy: A new paradigm for managing malignant brain cancer, Cancer Lett. (2014)dx.doi.org/10.1016/j.canlet.2014.07.015

Thomas N. Seyfried a,⇑, Roberto Flores a, Angela M. Poff b, Dominic P. D’Agostino b, Purna Mukherjee a

a Biology Department, Chestnut Hill, MA, USAb Department of Molecular Pharmacology and Physiology, University of South Florida, 33612 Tampa, FL, USA

a r t i c l e i n f o a b s t r a c t

Article history:Received 10 February 2014Received in revised form 9 July 2014Accepted 10 July 2014Available online xxxx

Keywords:Caloric restrictionBrain tumorEnergy metabolismGliomaKetogenic diet

Little progress has been made in the long-term management of glioblastoma multiforme (GBM), consid-ered among the most lethal of brain cancers. Cytotoxic chemotherapy, steroids, and high-dose radiationare generally used as the standard of care for GBM. These procedures can create a tumor microenviron-ment rich in glucose and glutamine. Glucose and glutamine are suggested to facilitate tumor progression.Recent evidence suggests that many GBMs are infected with cytomegalovirus, which could furtherenhance glucose and glutamine metabolism in the tumor cells. Emerging evidence also suggests that neo-plastic macrophages/microglia, arising through possible fusion hybridization, can comprise an invasivecell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells, as well as forthe more rapidly proliferating cancer stem cells. Therapies that increase inflammation and energy metab-olites in the GBM microenvironment can enhance tumor progression. In contrast to current GBM thera-pies, metabolic therapy is designed to target the metabolic malady common to all tumor cells (aerobicfermentation), while enhancing the health and vitality of normal brain cells and the entire body. The cal-orie restricted ketogenic diet (KD-R) is an anti-angiogenic, anti-inflammatory and pro-apoptotic meta-bolic therapy that also reduces fermentable fuels in the tumor microenvironment. Metabolic therapy,as an alternative to the standard of care, has the potential to improve outcome for patients with GBMand other malignant brain cancers.

� 2014 Published by Elsevier Ireland Ltd.

Glioblastoma multiforme (GBM)

GBM is the most malignant of the primary brain cancers withonly about 12% of patients surviving beyond 36 months (long-termsurvivors) [1–3]. Most glioblastomas are heterogeneous in cellularcomposition consisting of tumor stem cells, mesenchymal cells,and host stromal cells [4–9]. Primary GBM can arise de novo,whereas secondary GBM is thought to arise from lower-grade gli-omas [6,10,11]. The timing and incidence of malignant progressionfrom low-grade glioma to GBM is variable and unpredictable [12].In addition to the neoplastic cell populations, tumor-associatedmacrophages/monocytes (TAM) also comprise a significant cellpopulation in GBM sometimes equaling the number of tumor cells[13–18]. TAM can contribute to tumor progression through release

of pro-inflammatory and pro-angiogenic factors [14,16,18,19].Moreover, many cells appearing as TAM might actually be neoplas-tic macrophages/microglia. Recent studies show that some neo-plastic cells within GBM stain positive for both markers ofastrocytes (GFAP) and macrophages (CD68, CD163) consistent withthe fusion hybrid hypothesis for origin of invasive/metastatictumor cells [20–25]. Although systemic metastasis is not commonfor GBM, GBM cells can be metastatic if given access to extraneuralsites [26–30]. Using the secondary structures of Scherer, the neo-plastic cells in GBM invade through the neural parenchyma wellbeyond the main tumor mass making complete surgical resectionsexceedingly rare [1,31–34].

Despite extensive analysis from the cancer genome projects, nomutation is known that is unique to GBM [35–37]. Although manyGBMs contain mutations in genes thought to provoke progression(epidermal growth factor receptor, tumor promoter p53, PTEN,etc.) these mutations were not found in all GBM evaluated [37].These observations are consistent with evidence from other tumorsdemonstrating the extensive genetic heterogeneity seen in mostcells of natural tumors [38]. Recent evidence also suggests that

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Fig. 1. Kaplan–Meier estimates of overall survival of patients with glioblastomamultiforme by treatment group. The two patient groups included radiotherapyalone (n = 278) and radiotherapy with temolozomide (n = 254). Overall patientsurvival has remained largely unchanged form the study published in 2005 [58].Reprinted with permission from [2].

2 T.N. Seyfried et al. / Cancer Letters xxx (2014) xxx–xxx

the somatic mutations seen in cancer cells can arise as downstreamsecondary effects of disturbed energy metabolism and are unlikelyto provide useful information for therapeutic treatment strategiesfor the majority of GBM patients [11,39,40]. The retrograde or mito-chondrial stress response can lead to genomic instability as theresult of protracted disruption of oxidative phosphorylation withgeneration of reactive oxygen species [41–48]. However, the corre-lation between IDH1 gene mutation status and survival for patientswith recurrent glioma is interesting [37,49]. IDH1 mutations havebeen shown to alter the enzymatic activity of the encoded protein,resulting in up-regulation of hypoxia inducible factor-1a (HIF-1a)[49,50]. HIF-1a plays an important role in the process of angiogen-esis while also supporting tumor cell survival and proliferation[49,51]. Although the properties of the IDH1 mutation would pro-mote tumor growth, IDH1 expression in glioma patients is associ-ated with increased survival [37,49]. It remains unclear how theIDH mutations confer a survival advantage. It is also unclear if theIDH1 mutation acts in gliomas as a tumor promoting oncogene, atumor inhibiting suppressor gene, or can act as both an oncogeneand suppressor gene [52]. This conundrum should not be surpris-ing, however, as Soto and Sonnenschein have indicated that whenit comes to the somatic mutation theory of cancer; something canbe anything and it opposite [53]. We and others suggest that target-ing the metabolic malady common to most neoplastic cells in thetumor will likely be more effective for management than in target-ing genetic differences that are not expressed in all cells of thetumor [39,54].

Standard of care for malignant glioma

The current standard of care for GBM and many malignant braincancers includes maximum surgical resection, radiation therapy,and chemotherapy [2,55–57]. The toxic alkylating agent, temozol-omide (TMZ), is the most common chemotherapy used for treatingGBM. The most common adverse events of TMZ exposure besideshematological toxicities are alopecia, nausea, vomiting, anorexia,headache, and constipation. These adverse effects have beendescribed on the NCI web site (http://www.cancer.gov/cancertop-ics/druginfo/fda-temozolomide), and in original research articles[58–60]. Recent evidence also indicates that TMZ and most otherchemotherapies currently approved by the FDA for cancer manage-ment can potentially facilitate tumor recurrence through an effecton the Janus kinase–signal transducers and activators of transcrip-tion (JAK–STAT) pathway [61]. Moreover, Johnson et al. recentlyreported that 6 of 10 patients treated with TMZ followed an alter-native evolutionary path to high-grade glioma [11]. At recurrence,these tumors were hypermutated and harbored driver mutationsin the RB (retinoblastoma) and Akt–mTOR pathways that borethe signature of TMZ-induced mutagenesis. These observationsare concerning and suggest that better approaches to GBM man-agement are needed.

Although high-dose perioperative corticosteroids (dexametha-sone) are not recommended in all cases [55], most GBM patientsreceive corticosteroids as part of the standard of care, which is oftenextended throughout the course of the disease [16,62,63]. The anti-angiogenic drug, bevacizumab (Avastin) can also be given to GBMpatients despite the Food and Drug Administration’s removal ofAvastin for breast cancer due to toxicity and lack of efficacy[64,65]. Bevacizumab treatment increases progression free survivalin GBM patients, but does not increase overall patient survival [66].There have been no major advances in GBM management for over50 years, though use of temozolomide has produced marginalimprovement in survival over radiation therapy alone [2,67].Despite conventional treatments, prognosis remains poor for mostpatients with high-grade brain tumors [1,3,56,67,68]. (Fig. 1 Stupp

Please cite this article in press as: T.N. Seyfried et al., Metabolic therapy: A newdx.doi.org/10.1016/j.canlet.2014.07.015

Fig. 2). Is it possible that the limitations of standard therapy pro-duce untoward effects that undermine efficacy by increasingaggressiveness of surviving tumor cells?

Mitochondrial abnormalities in malignant brain tumors

Substantial evidence collected from numerous investigatorsover many years indicates that abnormalities in mitochondrialstructure and function are the hallmark of most cancers includingbrain cancer [69–74]. These mitochondrial abnormalities willreduce energy production through oxidative phosphorylation(OxPhos) [69–72,75–86]. Although pathological mitochondrialDNA (mtDNA) mutations were not found in a broad range of mousebrain tumors [87], recent studies identified potential pathologicalmutations in mtDNA from human GBM that were correlated withtumor origin [88]. The work of several investigators showed thatthe ultra structure of mitochondria in malignant brain tumors dif-fers markedly from the ultra structure of normal tissue mitochon-dria [78,79,89–92]. In contrast to normal mitochondria, whichcontain numerous cristae, mitochondria from GBM tissue samplesshowed swelling with partial or total cristolysis (Fig. 2). Cristaecontain the proteins of the respiratory complexes, and play anessential structural role in facilitating energy production throughOxPhos [93]. Many of the mitochondrial defects seen in excisedtumor tissue, however, are not often seen in the cell lines derivedfrom the tumor tissue. This is thought to arise from the abnormalin vitro growth environment that selects for cells with some levelof mitochondrial function [39].

The structural defects in human glioma mitochondria seen intissue sections are consistent with lipid biochemical defects inmurine gliomas. We showed that cardiolipin was abnormal in fiveindependently derived mouse brain tumors [94,95]. These tumorsarose spontaneously in the brains of inbred VM mice or wereinduced in C57/BL6 mice with 20-methylcholanthrene implanta-tion into the brain as we previously described [96,97]. Cardiolipinis the signature lipid of the inner mitochondrial membrane andcontrols the efficiency of OxPhos. Any alterations in the contentor fatty acid composition of cardiolipin will reduce cellular respira-tion [98–100]. No tumors have been found to our knowledge thatcontain a normal content or composition of cardiolipin. In additionto these findings, Poupon and colleagues also indicated that thehigh glycolytic activity seen in malignant gliomas could arise frommitochondrial structural abnormalities [101]. Despite abnormali-ties in mitochondrial structure and function, TCA cycle activity

paradigm for managing malignant brain cancer, Cancer Lett. (2014), http://

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cristolysis

Fig. 2. Typical ultrastructure of a normal mitochondrion and a mitochondrion from GBM tissue. Normal mitochondria contain elaborate cristae, which are extensions of theinner membrane and contain the protein complexes of the electron transport chain necessary for producing ATP through OxPhos. The mitochondrion from the GBM (m) isenlarged and shows a near total breakdown of cristae (cristolysis) and an electron-lucent matrix. The absence of cristae in GBM mitochondria indicates that OxPhos would bedeficient. The arrow indicates an inner membrane fold. Bar: 0.33 lm. Method of staining: uranyl acetate/lead citrate. The GBM mitochondrion was reprinted with permissionfrom Journal of Electron Microscopy [79]. The normal mitochondria and diagram were from http://academic.brooklyn.cuny.edu/biology/bio4fv/page/mito.htm. This figure waspreviously cited [65].

T.N. Seyfried et al. / Cancer Letters xxx (2014) xxx–xxx 3

can be robust in the mitochondria of some GBM [102]. The elevatedlactate production in these cells, however, would be indicative ofinsufficient respiration despite having robust TCA activity [39].Hence, substantial morphological and biochemical evidence existsshowing that respiratory capacity is defective to some degree inmost gliomas.

Based on numerous findings in human glioma cell lines and tis-sues, several research groups suggested that the majority of malig-nant brain tumors are incapable of producing adequate amounts ofenergy through oxidative phosphorylation [78,79,91,92,101,103–105]. Besides these ultrastructure findings, Renner and co-workersshowed that tumor cells isolated from human GBM could produceATP in the presence of potassium cyanide [106]. Cyanide blocks cyto-chrome c oxidase and kills normal control cells, which obtain energythrough OxPhos. Mitochondrial energy production in the presence ofcyanide suggests that OxPhos is not likely the origin of the energyproduced in these GBM cells. These and other studies suggest thatOxPhos is deficient in malignant gliomas and that energy throughoxidative metabolism alone would be incapable of maintaining via-bility in glioma cells [107].

The Warburg effect in malignant brain tumors

Otto Warburg first proposed that all cancers arise from irrevers-ible damage to cellular respiration. As a result, cancer cells increasetheir capacity to ferment lactate even in the presence of oxygen inorder to compensate for their insufficient respiration [108,109].Although confusion has surrounded Warburg’s hypothesis on theorigin of cancer cells [39,110,111], his hypothesis has never beenformally disproved and remains a credible explanation for the ori-gin of tumor cells [39,84,112–114]. Consequently, Warburg’sexplanation for the origin of cancer can no longer be viewed as ahypothesis, but can now be viewed as a theory [39,40].

The key points of Warburg’s theory are; (1) insufficient respira-tion initiates tumorigenesis and ultimately cancer, (2) energythrough glycolysis gradually compensates for insufficient energythrough respiration, (3) cancer cells continue to ferment lactatein the presence of oxygen, and (4) respiratory insufficiency eventu-ally becomes irreversible [108,109,115–117]. Warburg referred tothe phenomenon of enhanced glycolysis in cancer cells as ‘‘aerobicfermentation’’ to highlight the abnormal production of lactate in


the presence of oxygen [108,109,115–117]. The ‘‘Warburg effect’’refers to the aerobic fermentation of cancer cells [113,114]. Sub-stantial evidence exists showing that gliomas avidly consume glu-cose and produce lactate [74,102,107,118]. This would be expectedfor any tumor cell with quantitative or qualitative or abnormalitiesin mitochondria. Although the abnormal energy metabolism andmitochondrial abnormalities seen in most cancers including gli-oma could arise in part through oncogenic modulation of metabo-lism [111], the data from the nuclear and mitochondrial transferexperiments seriously challenge this possibility [39,119].

The nuclear cytoplasmic transfer experiments date back to 1969when McKinnell et al. showed that normal frogs could be clonedfrom the nucleus of a frog kidney tumor cell implanted into a fer-tilized egg [120,121]. The Mintz group showed that mice could becloned from the nuclei of teratomas, while Morgan and colleaguesshowed that differentiated post-implantation mouse embryoscould be cloned from the nuclei of medulloblastoma [122–124].The work of Jaenisch and colleagues showed that nuclei fromnumerous tumor types could support early development of mouseembryos without signs of abnormal cell proliferation [125]. Thesestudies were supported from numerous other studies in mouseand human cybrid cells showing that normal cytoplasm could sup-press tumorigenesis when combined with tumor nuclei [119]. Onthe other hand, tumors could arise when a normal nucleus wasplace into an enucleated tumor cytoplasm [126,127]. The studyof Howell and Sager recognized that these phenomena supportedWarburg’s original hypothesis that tumor cells arise from abnor-malities in the mitochondria rather than from abnormalities inthe nucleus [128]. The distinguished British geneticist Darlingtonalso presented evidence showing that tumor cells arose fromdefects in the cytoplasm and not the nucleus [129]. These observa-tions indicate that nuclear gene mutations are not the drivers oftumorigenesis and that normal mitochondria can suppress tumor-igenesis [130]. A comprehensive discussion of these findings inrelationship to the origin of cancer has appeared [119]. It is antic-ipated that the cancer field will move forward in new directionsonce the implications of these findings become more widelyrecognized.

As the result of insufficient respiration, cancer cells must rely onnon-oxidative energy metabolism to maintain energy balance andviability. Consequently, aerobic fermentation plays a role in


http://academic.brooklyn.cuny.edu/biology/bio4fv/page/mito.htm




producing energy through substrate level phosphorylation in thecytoplasm (glycolysis) [84,85,116,131]. Besides aerobic fermenta-tion in the cytoplasm, TCA cycle substrate level phosphorylationmight also produce ATP through non-oxidative metabolism.[132–135]. Amino acid fermentation can generate energy throughTCA substrate level phosphorylation under hypoxic conditions[134–137]. Hochachka showed that succinate is a waste productof amino acid fermentation [138,139]. Succinate is expressed intumor cells and is thought to inhibit a family of prolyl hydroxy-lases, which facilitate Hif-1a degradation through the von Hip-pel–Lindau (VHL) gene product [140]. Hif-1a stabilization inhibitsmitochondrial respiration and facilitates aerobic fermentation(Warburg effect) through its action on several glycolytic pathways[51,141,142]. It can be difficult to determine, however, the degreeto which mitochondrial ATP production arises from coupled respi-ration or from TCA cycle substrate level phosphorylation. Emergingevidence also indicates that the function of DNA repair enzymesand the integrity of the nuclear genome are dependent to a largeextent on the energy derived from normal respiration[41,42,143–149]. Previous studies in yeast and mammalian cellsshow that disruption of mitochondrial function can cause muta-tions (loss of heterozygosity, chromosome instability, and epige-netic modifications) in the nuclear genome [149–151]. Thesestudies suggest that genomic instability could arise from a pro-tracted reliance on non-oxidative energy. The process by whichsubstrate level phosphorylation could be linked to the hallmarksof cancer was discussed [39,84,85,152]. It remains speculativewhether respiratory insufficiency is irreversible, as Warburg sug-gested, or might be reversed through metabolic therapy. It is diffi-cult to imagine, however, how respiration or the mitochondriacristolysis seen in GBM could be easily reversed (Fig. 2).

Role of glucose and glutamine in brain tumor progression

Glucose is the predominant fuel of the brain, but also fuels tumorcell glycolysis as well as serving as a precursor for glutamate synthe-sis [107,109,153,154]. Using linear regression analysis, we showedthat the growth rate of the CT-2A experimental mouse astrocytomawas directly dependent on blood glucose levels [153]. The higherthe blood glucose levels, the faster the tumors grew. As glucose lev-els fall, tumor size and growth rate falls. Hyperglycemia not onlycontributes to rapid tumor cell growth, but also enhances whitematter damage in patients receiving radiation therapy [155]. Hyper-glycemia was also directly linked to poor prognosis in humans withmalignant brain cancer [156,157]. In other words, our findings inmice were corroborated with similar findings in humans.

Moreover, we found that the expression of insulin-like growthfactor 1 (IGF-1) was also dependent in part on circulating glucoselevels [51,153]. IGF-1 is a cell surface receptor linked to rapidtumor growth through the PI3K/Akt signaling pathway [51]. Theassociation of plasma IGF-1 levels with tumor growth rate is duein part to elevated levels of blood glucose. These findings in animalmodels and in brain cancer patients indicate that tumor growthrate and prognosis is dependent to a significant extent on circulat-ing glucose levels. Glucose is the prime fuel for glycolysis, whichdrives growth of most brain cancers [101,104,107]. As long as cir-culating glucose levels remain elevated, brain tumor growth willbe difficult to manage.

In addition to glucose, glutamine is also suggested to play an rolein tumor energy metabolism [158–161]. In contrast to extracranialtissues where glutamine is the most available amino acid, glutamineis tightly regulated in the brain through its involvement in the glu-tamate–glutamine cycle of neurotransmission [154,162]. Glutamateis a major excitatory neurotransmitter that must be cleared rapidlyfollowing synaptic release in order to prevent excitotoxic damage toneurons [162,163]. Glial cells possess transporters for the clearance


of extracellular glutamate, which is then metabolized to glutaminefor delivery back to neurons. Neurons metabolize the glutamine toglutamate, which is then repackaged into synaptic vesicles for futurerelease [162]. The glutamate–glutamine cycle maintains low extra-cellular levels of both glutamate and glutamine in normal neuralparenchyma. Disruption of the glutamate–glutamine cycle can pro-vide neoplastic GBM cells access to glutamine as we recentlydescribed [16].

Cytomegalovirus: an onco-modulator of brain tumor energymetabolism

Many cancers including GBM are infected with human cytomeg-alovirus (HCMV), which acts as an oncomodulator of tumor pro-gression [164–168]. Onco-modulation differs from initiation infacilitating progression after tumor initiation. The infection appearsto be localized to the tumor cells and not to normal cells [167].Products of the virus can damage mitochondria in the infectedtumor cells thus contributing to a further dependence on glucoseand glutamine for energy metabolism [169–172]. The virus ofteninfects cells of monocyte/macrophage origin, which are consideredthe origin of many metastatic cancers [25,173–175]. Indeed, weproposed that neoplastic microglia/macrophages were the mostinvasive cells within GBM [24]. GBM malignancy is correlated withthe titer of HCMV infection. The higher is the viral titer, the greateris the malignancy [168]. We suggest that HCMV infection in theseneoplastic cells will contribute to the progression of GBM throughan effect on tumor cell energy metabolism.

Does the current standard of care accelerate GBM recurrenceand progression through effects on energy metabolism?

It is our view that the current standard of care for managing GBMand other malignant brain cancers will contribute to tumor recur-rence and progression. This prediction comes from informationdescribing how the standard of care can enhance the availabilityof glucose and glutamine within the tumor microenvironment[16,130,176]. It is well documented that neurotoxicity frommechanical trauma (surgery), radiotherapy, and chemotherapy,can increase tissue inflammation and glutamate levels [32,177–179]. Local astrocytes rapidly clear extracellular glutamate metabo-lizing it to glutamine for release to neurons. In the presence of deador dying neurons, however, surviving tumor cells and the tumor-associated macrophages (TAMs) will use astrocyte-derived gluta-mine for their energy and growth. TAMs also release pro-angiogenicand growth factors, which further stimulate tumor progression[16,18,180]. Radiation damage to tumor cell mitochondria will has-ten a dependence on glucose and glutamine for growth and survival[84,109]. Both TAM and neoplastic microglia/macrophages couldpossibly ferment glutamine leading to the formation of succinate,a waste product of glutamine fermentation that contribute to localinflammation [132,181]. The HCMV infection in the neoplastic GBMcells will further accelerate tumor cell growth through increasedmetabolism of glucose and glutamine [169]. Tumor radiation willexacerbate the HCMV infection while also up-regulating the PI3K/Akt signaling pathway, which will drive glioma glycolysis and che-motherapeutic drug resistance [84,165,182–185]. In contrast tonormal glia that metabolize glutamate to glutamine, neoplastic gli-oma cells secrete glutamate [163]. It is not clear if the secreted glu-tamate is derived from glutamine in the necrotic microenvironmentor is synthesized from glucose. Glioma glutamate secretion isthought to contribute in part to neuronal excitotoxicity and tumorexpansion [163]. These observations indicate that the current stan-dard of care creates a metabolic environment that would rescueneoplastic cells and facilitate GBM progression.





In addition to the enhancing effects of radiation and HCMV onGBM energy metabolism, most GBM patients are also given high-dose glucocorticoids (dexamethasone) [63]. Although dexametha-sone is given to reduce radiation-associated brain swelling andtumor edema, dexamethasone significantly elevates blood glucoselevels [184,186–188]. Glucose fuels tumor cell glycolysis as well asserving as a precursor for glutamate synthesis [107,109,153,154].Many GBM patients are also treated with the anti-angiogenic drugbevacizumab (Avastin). Bevacizumab targets leaky blood vesselsthus enhancing hypoxia and radiation-induced necrosis in thetumor microenvironment. Increased hypoxia will further enhancetumor cell glycolysis and select for neoplastic microglia/macro-phages with greatest invasive properties [24,189–191]. Asmacrophages/microglia evolved to survive in hypoxic environ-ments, therapies that enhance hypoxia, like bevacizumab and radi-ation, will contribute to tumor progression. Bevacizumab alsoexacerbates radiation-induced necrosis, which will create a morefavorable environment for tumor recurrence [192]. Viewed collec-tively, these findings illustrate how the current standard of carewill create a microenvironment that facilitates the energy needsof tumor cells and the inevitable recurrence of the tumor. It isnot clear if those who administer the standard of care to gliomapatients are aware of these issues, as the standard of care hasremained largely unchanged for decades [1]. The key processesare illustrated in Fig. 3.

Although the existing standard of care for malignant brain cancerwill increase patient survival over the short term (months) com-pared to the ‘‘no therapy’’ option, it is clear how this therapeuticstrategy could accelerate the energy metabolism of surviving tumorcells. Moreover, the malignant phenotype of brain tumor cells thatsurvive radiotherapy is often greater than that of the cells fromthe original tumor [165,184]. Treatments that increase tumorenergy metabolism will facilitate tumor cell growth and survival,thus decreasing overall patient survival. In a randomized phase IIIstudy, none (0/278) of the patients receiving radiation alone

Fig. 3. How the standard of care can accelerate brain tumor growth and recurrence. GBMas TAMs, which release proinflammatory and pro-angiogenic factors. All these cells wisurvival. Recent evidence suggests that nearly all GBM are infected with human cytomIncreased glutamate (Glu) concentrations will arise after radiation/drug-induced necrosihyperglycemia will arise after corticosteroid (dexamethasone) therapy. Together, thesegrowth, survival, and the likelihood of tumor recurrence [16]. With permission from La


survived, whereas only about 2% (6/254) of patients receiving radi-ation and TMZ became long-term survivors [2] (Fig. 1). While GBMis certainly a deadly disease, it remains to be determined if the cur-rent standard of care contributes to an irreversible progression ofthe disease [1,2,165]. These findings address the general inadequacyof current therapies in providing long-term management of GBM.The slight improvement of patient survival with TMZ is interestingin light of findings showing that TMZ enhances the number of drivermutations in the tumor tissue [11]. Driver mutations are thought toprovoke tumor progression by conferring a growth advantage to themost neoplastic cells [36,37,193–195]. These findings question therole of driver mutations and tumor progression and also questionthe gene theory of cancer [130]. Is it possible that the toxic effectsof TMZ (fatigue, nausea, diarrhea, etc.) cause an indirect calorierestriction, which thus improves survival?[196]. Further studieswould be needed to determine if TMZ improves patient survivalthrough indirect effects from calorie restriction. As long as braincancer is viewed as something other than a metabolic disease, therewill be little progress in improving progression free survival in ouropinion [130,180]. The current standard of care for GBM offers littlehope of long-term patient survival. This situation is even more dis-turbing, as the standard of care is not considered curative, but onlypalliative [197]. If GBM becomes viewed as a metabolic disease,however, we might anticipate major advances in treatment andsubstantial enhancement of progression free survival.

Exploiting mitochondrial dysfunction for the metabolic managementof GBM

GBM, like most cancers, can be considered primarily a disease ofenergy metabolism [40,65,198]. Rational strategies for GBM man-agement should therefore be found in therapies that specificallytarget tumor cell energy metabolism. As glucose is the major fuelfor tumor energy metabolism through lactate fermentation, therestriction of glucose becomes a prime target for GBM manage-

and other high-grade brain tumors consist of multiple neoplastic cell types as wellll use glucose and glutamine (Gln) as major metabolic fuels for their growth andegalovirus, which enhances glucose and glutamine metabolism in the tumor cells.s. Reactive astrocytes (RA) take up and metabolize glutamate to glutamine, whereas

standard treatments will provide a microenvironment that facilitates tumor cellncet Oncology.




Fig. 4. Relationship of circulating levels of glucose and ketones (b-hydroxybutyrate,b-OHB) to tumor management. The glucose and ketone values are within normalphysiological ranges under fasting conditions in humans and will produce anti-angiogenic, anti-inflammatory, and pro-apoptotic effects. We refer to this state asthe zone of metabolic management. Metabolic stress will be greater in tumor cellsthan in normal cells when the whole body enters the metabolic zone. The values forblood glucose in mg/dl can be estimated by multiplying the mM values by 18. Theglucose and ketone levels predicted for tumor management in human cancerpatients are 3.1–3.8 mM (55–65 mg/dl) and 2.5–7.0 mM, respectively. These ketonelevels are well below the levels associated with ketoacidosis (blood ketone valuesgreater than 15 mmol). Elevated ketones will sustain metabolic pressure on tumorcells, buffer daily fluctuations in blood glucose levels, and protect the brain fromhypoglycemia. Modified from a previous version [258].


ment. However, most normal cells of the brain also need glycolyticpathway products, such as pyruvate, for energy productionthrough OxPhos. It therefore becomes important to protect normalbrain cells from drugs or therapies that disrupt glycolytic pathwaysor cause systemic reduction of glucose [130]. It is well known thatketones can replace glucose as an energy metabolite and can pro-tect the brain from severe hypoglycemia [199–201]. Hence, theshift in energy metabolism associated with a low carbohydrate,high-fat ketogenic diet administered in restricted amounts (KD-R) can protect normal brain cells from glycolytic inhibition andthe brain from hypoglycemia.

When systemic glucose availability becomes limiting, most nor-mal cells of the body will transition their energy metabolism to fatsand ketone bodies. Ketone bodies are generated almost exclusivelyin liver hepatocytes largely from fatty acids of triglyceride originduring periods of fasting [199,202]. The brain is exceptionallycapable of transitioning from the metabolism of glucose to themetabolism of ketone bodies (b-hydroxybutyrate and acetoace-tate) during periods of prolonged fasting [203–206]. The metabo-lism of ketones is an evolutionary adaptation that allows thebody and brain to function at a high state of efficiency when foodis unavailable [203]. A restriction of total caloric intake will facili-tate a reduction in blood glucose and insulin levels and an eleva-tion in ketone bodies. As long as the body is in a state ofphysiological ketosis (2–7 mM ketones in blood) blood glucose lev-els can be reduced to very low levels (2–3 mM) without producingthe adverse effects of hypoglycemia [207]. Recent studies indicatethat b-OHB is a histone deacetylase inhibitor that can reduce oxi-dative stress in normal cells through effects on the FOX3A andMT2 transcription factors [208]. Many tumors including gliomas,however, have reduced activity of succinyl-CoA: 3-ketoacid CoAtransferase, the rate-controlling step for utilizing b-OHB as a respi-ratory fuel [209–214]. Defects in this enzyme will limit the abilityof tumor cells to utilize ketone bodies as an alternative fuel to glu-cose. Metabolic stress following the gradual replacement of glu-cose with ketone bodies will be therefore greater in tumor cellsthan in normal cells [215]. Our group and others showed thatketone bodies could also be toxic to some cancer cells[39,209,216,217]. Nutritional ketosis induces metabolic stress ontumor tissue that is selectively vulnerable to glucose deprivation[65]. Hence, metabolic stress will be greater in tumor cells thanin normal cells when the whole body is transitioned away fromglucose and to ketone bodies for energy.

The metabolic shift from glucose metabolism to ketone bodymetabolism creates an anti-angiogenic, anti-inflammatory, andpro-apoptotic environment within the tumor microenvironment[153,196,218–221]. Calorie restriction and ketogenic diets lowerglucose and elevate ketones, which can account in part for thetherapeutic benefit of these approaches [153,176,210,222]. Thegeneral concept of a survival advantage of tumor cells over normalcells occurs when fermentable fuels are abundant, but not whenthey become limiting [223]. Fig. 4 illustrates the theoreticalchanges in whole body levels of blood glucose and ketone bodies(b-hydroxybutyrate) that will metabolically stress tumor cellswhile enhancing the metabolic efficiency of normal cells. The effi-cacy of this therapeutic strategy was illustrated previously in can-cer patients and in preclinical models [210,224–228].

The calorie restricted ketogenic diet as a non-toxic metabolictherapy for brain cancer

Emerging evidence suggests that metabolic therapies usingketogenic diets that lower glucose levels can help retard GBMgrowth in younger and older patients [227–229]. Restricted dietsare those that deliver fewer total calories in order to lower circulat-


ing glucose and insulin levels. We found that the KD reduced braincancer growth and angiogenesis in mice only when administeredin restricted amounts [65,153,210]. The importance of this pointcannot be overemphasized, as unrestricted KD administrationwas largely without effect on the growth of the CT-2A astrocytoma[153,210]. We also showed that CR alone could reduce inter-hemi-spheric invasion through the ‘‘Secondary Structures of Scherer’’ in anatural mouse model of GBM [230]. In contrast to restrictedadministration, blood glucose levels remain high and ketones arelargely excreted in the urine when the KD is fed to mice in unre-stricted amounts. Blood ketone levels are also higher when theKD is administered in restricted than in unrestricted amounts.Harik et al. also showed that unrestricted feeding of the KD hadno significant effect on brain glucose metabolism in rats [231].However, Scheck and colleagues reported growth inhibition ofthe mouse GL261 cells from an unrestricted KD suggesting thatsome tumors might be susceptible to KD growth inhibition withoutcalorie restriction or reduction [225]. On the other hand, glucosewas reduced in mice receiving an unrestricted KD administeredtogether with radiation therapy [222]. In contrast, we found thatunrestricted consumption of the KD was ineffective in reducingtumor growth or angiogenesis in the syngeneic CT-2A glioma[153,210]. The unrestricted feeding of the KD prevented glucoseand ketones from reaching the therapeutic levels necessary forblocking angiogenesis and enhancing tumor cell apoptosis[153,210]. Dyslipidemia and insulin insensitivity can also occurin association with the unrestricted feeding of the KD in mice[232]. We documented the importance of calorie restriction formanagement of mouse and human astrocytoma growth usingeither a standard high carbohydrate diet or a KD [210,219]. Dueto differences in basal metabolic rate between man and mouse,water-only therapeutic fasting in man would be equivalent to a40% CR in mice [233]. As the KD-R produces metabolic effects sim-ilar to that of water-only fasting, it is our opinion that it will be eas-ier for people to implement and comply with the KD-R than withwater-only fasting. To avoid the possibility of dyslipidemia andinsulin insensitivity, we believe that the therapeutic benefits ofthe KD will also be best in humans if consumed in restricted





amounts, but in sufficient quantities to maintain energy levels andlean body mass.

Nebeling and co-workers first showed that the restricted KDwas an effective non-toxic management for advanced stage astro-cytoma in children [228]. The malignant brain tumors in the twochildren of this study were largely unresponsive to the standardof care, which caused significant toxicity to both children. Thestandard of care was discontinued in one child (#1) and reducedin the other (#2), as the children were administered a mediumchain triglyceride KD that lowered blood glucose and elevatedblood ketone bodies [228]. Ketone bodies (b-hydroxybutyrateand acetoacetate) become an alternative fuel for brain energymetabolism when glucose levels are reduced [199,205,234,235].Ketone bodies have known neuroprotective and anti-inflammatoryaction against a number of neurological and neurodegenerativediseases [236]. Ketone body metabolism increases the redox spanof the Co-Q couple thereby enhancing the proton motive gradientand reducing the production of ROS [201,235]. Ketone body metab-olism reduces ROS while enhancing metabolic efficiency of normalcells [225,235–238]. In addition to providing an alternative fuel toglucose, b-hydroxybutyrate also acts as a histone deacetylaseinhibitor, which could reduce glucose and glutamine metabolism[208,237]. It is also important to recognize that circulating ketonelevels will rarely exceed 7–9 mmol in most non-diabetic patientssince excess ketones will be excreted in the urine [235]. Hence,ketones are considered ‘‘good medicine’ for several neurologicaland neurodegenerative diseases [199,205,239].

The health status of both children in the Nebeling et al. studyimproved after initiation of the ketogenic diet and overall survivalwas longer than initially predicted [228]. The quality of lifeimproved significantly for the adult GBM patient in the Zuccoliet al. study while she remained on a calorie restricted KD [227].Although this patient experienced radiological resolution whileon the KD, the tumor recurred after the diet was discontinued[227]. The KD administered to the GBM patients in the study ofChamp et al., appeared to improve response to the standard of care[229]. These observations are consistent with those from Schecket al. in showing that survival was greater in mice with GBM thatreceived radiotherapy with the KD than in mice that receivedradiotherapy alone [222,240]. The results from these case reportsand preclinical studies suggest that the KD can be effective inimproving overall survival and quality of life in children and adultswith malignant brain cancer.

In addition to lowering glucose availability to the tumor micro-environment, the KD could potentially lower brain glutamine lev-els thus restricting availability of this energy metabolite for tumorgrowth [237,241,242]. The KD-R could be even more therapeutic ifcombined with non-toxic drugs that also target glycolysis, e.g., 2-deoxyglucose or 3-bromopyruvate, and dichloroacetate (DCA)[243–245]. The KD-R might also further enhance GBM patient sur-vival when combined with the anti-human cytomegalovirus(HCMV) drug, valganciclovir. HCMV infection of tumor cells con-tributes to elevated metabolism of glucose and glutamine[169,246]. Recent evidence indicates that valganciclovir canenhance survival of GBM patients [247].

Poff et al. also recently showed a synergistic interactionbetween the KD and hyperbaric oxygen therapy (HBO2T) [248].The KD reduces glucose for glycolytic energy, while also reducingNADPH levels for anti-oxidant potential through the pentose-phos-phate-pathway. HBO2T will increase ROS in the tumor cells whilethe ketones protect normal cells against ROS damage and frompotential oxygen toxicity [201,235]. Glucose deprivation willenhance oxidative stress in tumor cells, while increased oxygencan reduce tumor cell proliferation [249,250]. HBO2T has beenused as a radiosensitizer for glioma patients with notable improve-ment over radiation alone [251]. In contrast to radiation therapy,


which also kills tumor cells through ROS production [252], theKD + HBO2T will kill tumor cells without causing toxic collateraldamage to normal cells. Some ketogenic diets might also enhancethe therapeutic action of radiation therapy against brain and lungtumors [222,253]. It is not yet known if therapeutic efficacy ofthe KD-R will be greater when combined with HBO2T than whencombined with radiation therapy. It will therefore be importantto compare and contrast the therapeutic efficacy of conventionalradiation therapy with HBO2T when used with the KD-R.

According to the evidence presented here, the KD-R can be aviable non-toxic option to the current standard of care for manag-ing malignant brain cancer. The KD-R can target tumor cells glob-ally without harming normal neurons and glia. The blood brainbarrier is less of an issue with the KD-R therapy than with conven-tional therapies. We showed that the KD-R could enhance drugdelivery to the brain [254]. Although radiotherapy was superiorto best supportive care in older patients (>70 years of age) withhigh-grade glioma, the definition of ‘‘best supportive care’’ isambiguous at best [255]. Would the KD-R + HBO2T be a better ther-apeutic option than radiotherapy or ‘‘best supportive care? Whichbrain tumor organizations might be interested in testing theseoptions?

Although metabolic therapy could be a more rational approachto malignant brain cancer management than is the current stan-dard of cancer, the KD-R is not without some shortcomings. Com-pliance can be a major obstacle in attempting to implement theKD-R [65]. Some people can have difficulty in maintaining bloodglucose and ketones in the ranges needed to target angiogenesisand to control tumor growth. Considerable patient discipline andmotivation is required for implementing the KD-R as a therapy[198]. However, administration of ketone esters could possiblyenable patients to circumvent the dietary restriction generallyrequired for sustained nutritional ketosis. Ketone ester-inducedketosis would make sustained hypoglycemia more tolerable andthus assist in metabolic management of cancer [39,256,257]. Itwould be helpful if more neurooncologists could become familiarwith the principles and concepts about how metabolic therapycontrols tumor growth and how this therapy can be used as analternative to the standard of care. This type of information isnot generally covered as part of the training in the field. Conse-quently, some glioma patients might be discouraged from usingthe KD-R. Nevertheless, we remain hopeful that the metabolicapproach to brain cancer management using the KD-R togetherwith synergistic drugs, and possibly HBO2T could offer a betterchance for improved quality of life and longer-term survival foryounger and older GBM patients. Will brain tumor organizationsstep forward to test our predictions?

Conflict of interest

None of the authors have a conflict of interest.

Acknowledgements

This work was supported in part from NIH - United StatesGrants (HD-39722, NS-1080 55195, and CA-102135), a Grant fromthe American Institute of Cancer Research, and the Boston CollegeExpense Fund. We thank Dr. Giulio Zuccoli and Jeremy Marsh forhelpful comments, which were included in our similar review pub-lished in ‘‘Oncology & Hematology Reviews’’ and cited as reference176 in the current review.

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Metabolic therapy: A new paradigm for managing malignant brain cancer