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Neurologic Oncology Glioblastoma Could Metabolic Therapy Become a Viable Alternative to the Standard of Care for Managing Glioblastoma? Thomas N Seyfried, PhD, 1 Jeremy Marsh, MSV, 2 Purna Mukherjee, PhD, 3 Giulio Zuccoli, MD 4 and Dominic P D’Agostino, PhD 5 1. Professor of Biology; 2 Bachelor of Science; 3. Research Assistant Professor, Biology Department, Boston College, Chestnut Hill, Massachusetts, US; 4. Section Chief, Section of Neuroradiology, Children’s Hospital of Pittsburgh, and Associate Professor of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, US; 5. Assistant Professor, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, US Abstract 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 9, 2014 Accepted: March 5, 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: Thomas.seyfried@bc.edu Glioblastoma Multiforme Glioblastoma multiforme (GBM) is the most malignant of the primary brain cancers with only about 12 % of patients surviving beyond 36 months (long- term 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 © To u ch MEd ica l MEdia 201 4 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 13