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Publications

Publications resulting from research funded by The Foundation for Metabolic Cancer Therapies.

Nontoxic Targeting of Energy Metabolism in Preclinical VM-M3 Experimental Glioblastoma:

Zachary M. Augur, Catherine M. Doyle, Mingyi Li, Purna Mukherjee and Thomas N. Seyfried* Thomas N. Seyfried Laboratory, Biology Department, Boston College, Chestnut Hill, MA, United States

Introduction: Temozolomide (TMZ) is part of the standard of care for treatingIntroduction: Temozolomide (TMZ) is part of the standard of care for treatingglioblastoma multiforme (GBM), an aggressive primary brain tumor. New approachesare needed to enhance therapeutic efficacy and reduce toxicity. GBM tumor cells aredependent on glucose and glutamine while relying heavily on aerobic fermentation forenergymetabolism. Restricted availability of glucose and glutaminemay therefore reducedisease progression. Calorically restricted ketogenic diets (KD-R), which reduce glucoseand elevate ketone bodies, offer a promising alternative in targeting energy metabolismbecause cancer cells cannot effectively burn ketones due to defects in the number,structure, and function of mitochondria. Similarly, oxaloacetate, which participates in thedeamination of glutamate, has the potential to reduce the negative effects of excessglutamate found in many brain tumors, while hyperbaric oxygen therapy can reverse thehypoxic phenotype of tumors and reduce growth. We hypothesize that the combinatorialtherapy of KD-R, hyperbaric oxygen, and oxaloacetate, could reduce or eliminate theneed for TMZ in GBM patients.
Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis:

Christos Chinopoulos1 and Thomas N. Seyfried

Introduction: Glioblastoma multiforme (GBM) carries the highest mortalityrate among primary brain tumors and remains largelyunmanageable. Life expectancy following diagnosis isonly about 12 to 14 months. This has changed little fordecades despite continuing research (Fisher and Buffler,2005; Krex et al., 2007; Stupp et al., 2009; Lawrence et al.,2011; Ahmadloo et al., 2013; Alexander and Cloughesy,2017). Indeed, a recent reevaluation found that overallsurvival for GBM is woefully similar to that reported byCushing almost a century ago (Fatehi et al., 2018). Adefining characteristic of GBM is the secondary structuresof Scherer, which include diffuse parenchymal growthinvasion over the subpial surface, along white mattertracks, and through the Virchow–Robin spaces (Scherer,1940; Laws et al., 1993; Kleihues and Ohgaki, 1999;
Management of Glioblastoma Multiforme in a patient treated With Ketogenic Metabolic therapy and Modified standard of Care: a 24-Month Follow-Up:

Ahmed M. A. Elsakka1, Mohamed Abdel Bary2, Eman Abdelzaher 3, Mostafa Elnaggar 4, Miriam Kalamian5, Purna Mukherjee6 and Thomas N. Seyfried6*

Few advances have been made in overall survival for glioblastoma multiforme (GBM)Few advances have been made in overall survival for glioblastoma multiforme (GBM)in more than 40 years. Here, we report the case of a 38-year-old man who presentedwith chronic headache, nausea, and vomiting accompanied by left partial motor seizuresand upper left limb weakness. Enhanced brain magnetic resonance imagingrevealed a solid cystic lesion in the right partial space suggesting GBM. Serum testingrevealed vitamin D deficiency and elevated levels of insulin and triglycerides. Prior tosubtotal tumor resection and standard of care (SOC), the patient conducted a 72-hwater-only fast. Following the fast, the patient initiated a vitamin/mineral-supplementedketogenic diet (KD) for 21 days that delivered 900 kcal/day.
Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer:

Mehmet Salih İyikesici , Abdul Kadir Slocum , Ayshe Slocum , Ferhan Bulent Berkarda , Miriam Kalamian , Thomas N. Seyfried

Triple-negative breast cancer (TNBC) is more aggressive and metastatic than other breastTriple-negative breast cancer (TNBC) is more aggressive and metastatic than other breastcancer types. Cytotoxic chemotherapy is presently the predominant systemic therapy for TNBCpatients. This case report highlights the influence of metabolically supported chemotherapy(MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT) in anoverweight 29-year-old woman with stage IV (T4N3M1) triple-negative invasive ductalcarcinoma of the breast. The patient presented with an observable mass in her left breastdetected during a physical examination in December 2015.
Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma:

Purna Mukherjee1, Zachary M. Augur1, Mingyi Li1, Collin Hill2, Bennett Greenwood2, Marek A. Domin3, Gramoz Kondakci2, Niven R. Narain2, Michael A. Kiebish2, Roderick T. Bronson4, Gabriel Arismendi-Morillo5, Christos Chinopoulos 6 & Thomas N. Seyfried1

Glioblastoma (GBM) is an aggressive primary human brain tumour that has resisted effectiveGlioblastoma (GBM) is an aggressive primary human brain tumour that has resisted effectivetherapy for decades. Although glucose and glutamine are the major fuels that drive GBMgrowth and invasion, few studies have targeted these fuels for therapeutic management. Theglutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with acalorically restricted ketogenic diet (KD-R) to treat late-stage orthotopic growth in twosyngeneic GBM mouse models: VM-M3 and CT-2A. DON targets glutaminolysis, while theKD-R reduces glucose and, simultaneously, elevates neuroprotective and non-fermentableketone bodies. The diet/drug therapeutic strategy killed tumour cells while reversing diseasesymptoms, and improving overall mouse survival.
Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?:

Thomas N. Seyfried1 · Laura Shelton2 · Gabriel Arismendi‑Morillo3 · Miriam Kalamian4 · Ahmed Elsakka5 · Joseph Maroon6 · Purna Mukherjee1

No major advances have been made in improving overall survival for glioblastoma (GBM) in almost 100 years. The currentNo major advances have been made in improving overall survival for glioblastoma (GBM) in almost 100 years. The currentstandard of care (SOC) for GBM involves immediate surgical resection followed by radiotherapy with concomitanttemozolomide chemotherapy. Corticosteroid (dexamethasone) is often prescribed to GBM patients to reduce tumor edemaand inflammation. The SOC disrupts the glutamate–glutamine cycle thus increasing availability of glucose and glutaminein the tumor microenvironment. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance anddrive GBM growth through substrate level phosphorylation in the cytoplasm and the mitochondria, respectively.