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Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?

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Abstract

No major advances have been made in improving overall survival for glioblastoma (GBM) in almost 100 years. The current standard of care (SOC) for GBM involves immediate surgical resection followed by radiotherapy with concomitant temozolomide chemotherapy. Corticosteroid (dexamethasone) is often prescribed to GBM patients to reduce tumor edema and inflammation. The SOC disrupts the glutamate–glutamine cycle thus increasing availability of glucose and glutamine in the tumor microenvironment. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive GBM growth through substrate level phosphorylation in the cytoplasm and the mitochondria, respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability while elevating ketone bodies that are neuroprotective and non-fermentable. Information is presented from preclinical and case report studies showing how KMT could target tumor cells without causing neurochemical damage thus improving progression free and overall survival for patients with GBM.

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Abbreviations

GBM:

Glioblastoma

TMZ:

Temozolomide

SOC:

Standard of care

KMT:

Ketogenic metabolic therapy

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Acknowledgements

The author would like to acknowledge support from the Foundation for Metabolic Cancer Therapies, the Claudia & Nelson Pleltz Foundation, Crossfit Inc., Lewis Topper, Edward Miller, Ellen Davis, and the Boston College research expense fund. The authors also thank Pedro Arteaga, Norkys Sanchez, and Gianny Arteaga (Maracaibo-Venezuela) for technical help with EM micrographs.

Funding

Funding was provided by Foundation for Metabolic Cancer Therapies (Grant No. 5101551), Claudia & Nelson Peltz Foundation and CrossFit (Grant No. 51o5681).

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Authors and Affiliations

  1. Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, MA, 02467, USA

    Thomas N. Seyfried & Purna Mukherjee

  2. Human Metabolome Technologies America, 24 Denby Rd., Boston, MA, 02134, USA

    Laura Shelton

  3. Instituto de Investigaciones Biológicas, Facultad de Medicina, Universidad del Zulia, Maracaibo, 526, Venezuela

    Gabriel Arismendi-Morillo

  4. Dietary Therapies Llc., Hamilton, MT, USA

    Miriam Kalamian

  5. Faculty of Medicine, University of Alexandria, Alexandria, Egypt

    Ahmed Elsakka

  6. Department of Neurosurgery, University of Pittsburgh Medical Center, Suite 5C, 200 Lothrop St., Pittsburgh, PA, USA

    Joseph Maroon

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Seyfried, T.N., Shelton, L., Arismendi-Morillo, G. et al. Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?. Neurochem Res 44, 2392–2404 (2019). https://doi.org/10.1007/s11064-019-02795-4

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