Thuy-Duyen Nguyen

Introduction. Glioblastoma Multiforme (GBM), an aggressive Type IV astrocytoma, is the most common primary brain tumor¹. Patients diagnosed with GBM undergo a rigorous cancer treatment that include tumor resection, radiotherapy, and temozomide.² Despite this, patients face a median survival of 12 – 15 months and an average survival rate of less than 5%.¹ Studies have found that GBMs exhibit the typical hallmarks of cancer, but to a magnified degree, which may allow for tumor recurrence despite current therapies. Some studies have associated the augmented characteristics to the upregulated Hypoxia Inducible Factor-1 (HIF-1) as a central player, in adapting GBM to new conditions.³ Due to hypoxic environments generated by the tumor’s aggressiveness and the treatments, HIF-1 especially aids in deregulating cellular energetics to provide energy and biomaterial for continued survival and growth, thus suggesting possible new therapeutic targets downstream of the HIF-1 pathway. Methods. Expression levels of HIF-1 and downstream proteins were compared between normoxic and hypoxic environments in GBM cell lines. Benefits of targeting of pyruvate dehydrogenase kinase-1 (PDK1) using dichloroacetate (DCA) and of altering tumor environments into a state of ketosis using the ketogenic diet (KD) in conjunction of current cancer treatments were assessed in GBM cell lines, athymic mice, and participating patients. Results. GBM cell lines demonstrated elevated expression of HIF-1 with expected increased levels of glucose transporter GLUT1 and glycolytic enzymes: PDK1, hexokinase 1 (HK2), and pyruvate kinase (PKM2)^4,5. The increase in glycolytic enzymes corresponded with a decreased expression of mitochondrial complex IV (cytochrome c) and ketolytic enzymes: 3-oxoacid CoA transferase (OXTC1) and D-beta-hydroxybutyrate dehydrogenase 1 (BDH1) ⁵. Targeting of PDK1 using DCA with radiation demonstrates increased ROS production, dsDNA breaks, and G2-M cell arrests⁶. Combining the ketogenic diet with chemotherapy, bevacizumab, improved the overall medial survival rate of athymic mice⁷. Conclusion. Studies have found elevated HIF-1 in GBM cell lines due to hypoxic environments have led to increased deregulation of cellular energetics where cancer cells rely on aerobic glycolysis evident by the increased levels of glycolytic enzymes with a corresponding decrease in levels of ketolytic enzymes. Additional targeting of the upregulated PDK1 levels and downregulated ketolytic enzymes due to increased expression of HIF-1 improved the efficacy of current GBM therapies and overall host survival rate.

1. Seyfried TN, Flores R, Poff AM, D’Agostino DP, Mukherjee P. Metabolic therapy: a new paradigm for managing malignant brain cancer. Cancer Lett. 2015;356(2 Pt A):289-300.
2. Eales KL, Hollinshead KE, Tennant DA. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis. 2016;5:e190.
3. Womeldorff M, Gillespie D, Jensen RL. Hypoxia-inducible factor-1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma. Neurosurg Focus. 2014;37(6):E8.
4. Han JE, Lim PW, Na CM, et al. Inhibition of HIF1alpha and PDK Induces Cell Death of Glioblastoma Multiforme. Exp Neurobiol. 2017;26(5):295-306.
5. Chang HT, Olson LK, Schwartz KA. Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: implication for ketogenic diet therapy. Nutr Metab (Lond). 2013;10(1):47.
6. Shen H, Hau E, Joshi S, Dilda PJ, McDonald KL. Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism. Mol Cancer Ther. 2015;14(8):1794-1804.
7. Rieger J, Bahr O, Maurer GD, et al. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol. 2014;44(6):1843-1852.