Abstract
Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano). Gene expression data show that GBM subtypes have similar glucose and FAO pathways, and GBM tumors have significant upregulation of enzymes in both pathways, compared to normal brain tissue (p < 0.01). DCA and the DCA/Rano combination showed reduced colony-forming activity of GBM and increased oxidative stress, DNA damage, autophagy, and apoptosis in vitro. In the orthotopic Gl261 and CT2A syngeneic murine models of GBM, DCA, Rano, and DCA/Rano increased median survival and induced focal tumor necrosis and hemorrhage. In conclusion, dual targeting of glycolytic and FAO metabolic pathways provides a viable treatment that warrants further investigation concurrently or as an adjuvant to standard chemoradiation for GBM.
Highlights
Glioblastoma (GBM) is a biologically heterogeneous and uniformly fatal disease
Further examination showed that the expression of selected targetable enzymes in the glycolytic pathway, pyruvate dehydrogenase kinase (PDK) 1–4, and the fatty acid oxidation (FAO) pathways, acetyl CoA dehydrogenase (ACAD), thiolase [acetyl-coenzyme A acetyltransferase (ACAT)], cronotase (ECH), and hydroxyacyl-CoA dehydrogenase (HADH), were expressed across the GBM subtypes, except enoyl-CoA hydratase (ECH) was significantly higher in proneural/neural compared to classical tumors (p = 0.0022; Figure 1B)
Contrary to a recent report by Duraj and colleagues [27], we show that glucose and FAO metabolic pathways are similar among GBM subtypes, and enzymes of the glycolytic and FAO pathways are upregulated in GBM tumors compared to normal brain tissues
Summary
Glioblastoma (GBM) is a biologically heterogeneous and uniformly fatal disease. Verhaak et al [1] describe classical, mesenchymal, neural, and proneural subtypes of GBM based on an 840 gene signature. These have been adopted as clinically relevant molecular subtypes with different disease progression and prognosis. While brain cancer makes up 1.3% of all new cancer diagnoses in Australia, it accounts for 3.2% of cancer-related deaths [2]. GBM accounts for 54% of brain cancer cases and has a 5-year survival rate
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