Abstract
First-line cancer therapies such as alkylating agents and radiation have limited survival benefits for Glioblastoma (GBM) patients. Current research strongly supports the notion that inhibition of aberrant tumor metabolism holds promise as a therapeutic strategy when used in combination with radiation and chemotherapy. Hexokinase 2 (HK2) has been shown to be a key driver of altered metabolism in GBM, and presents an attractive therapeutic target. To date, no study has fully assessed the therapeutic value of targeting HK2 as a mechanism to sensitize cells to standard therapy, namely in the form of radiation and temozolomide (TMZ). Using cell lines and primary cultures of GBM, we showed that inducible knockdown of HK2 altered tumor metabolism, which could not be recapitulated by HK1 or HK3 loss. HK2 loss diminished both in vivo tumor vasculature as well as growth within orthotopic intracranial xenograft models of GBMs, and the survival benefit was additive with radiation and TMZ. Radio-sensitization following inhibition of HK2 was mediated by increased DNA damage, and could be rescued through constitutive activation of ERK signaling. This study supports HK2 as a potentially effective therapeutic target in GBM.
Highlights
Glioblastoma (GBM) is the most common and malignant primary brain tumor, with a median survival of only 12–16 months despite aggressive therapies including surgery, radiation and chemotherapy using alkylating agents such as temozolomide (TMZ) [1, 2]
Using The Cancer Genome Atlas (TCGA) data set of 529 samples, we selected the top and bottom 10% of Hexokinase 2 (HK2) expressing patient samples (n = 50 per group) at the RNA level to identify molecular or clinically aggressive features of GBM associated with HK2 (Figure 1A)
The high HK2 expressing cohort were significantly enriched for mutations or copy number alterations in PTEN, TP53 and RB1, while low HK2 expressing TCGA patient samples were enriched in isocitrate dehydrogenase-1 (IDH1) mutations (Figure 1H)
Summary
Glioblastoma (GBM) is the most common and malignant primary brain tumor, with a median survival of only 12–16 months despite aggressive therapies including surgery, radiation and chemotherapy using alkylating agents such as temozolomide (TMZ) [1, 2]. GBM and many other cancers undergo metabolic adaptation and reprogramming, favoring a shift towards anabolic metabolism, with elevated aerobic glycolysis and oxidative phosphorylation (OXPHOS) This metabolic shift confers several tumorigenic advantages to GBMs, namely provision of biomass/macromolecules for growth, as well as production of excess lactate that favors tumor cell invasion and adaptation to unfavorable microenvironmental conditions like hypoxia or chemotherapy. In low-grade gliomas and secondary GBM, highly recurrent mutations are observed in a key metabolic enzyme, isocitrate dehydrogenase-1 (IDH1) [5, 6] These hot-spot mutations result in a single amino acid substitution from arginine to histidine at position 132 (R132H), which leads to neomorphic activity of IDH1, and production of the onco-metabolite 2-hydroxyglutaric acid (2-HG), which in turn results in aberrant DNA methylation [7,8,9,10]
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