GENE-21. THE KETOGENIC DIET ALTERS THE EPIGENETIC LANDSCAPE OF GBM TO POTENTIATE THE EFFECTS OF CHEMO AND RADIOTHERAPY

Glioblastoma Multiforme (GBM) is the most aggressive form of primary brain tumor, with a median survival time of just 14 months. Although a number of targeted therapies have been devised for these tumors, they have proved to be ineffective due to the high degree of inherent heterogeneity exhibited b...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2017-11, Vol.19 (suppl_6), p.vi96-vi97
Main Authors: Tzouliana, Stylianou, Hajji, Nabil, Perryman, Richard, O’Neill, Kevin, Woolf, Eric C, Scheck, Adrienne C, Syed, Nelofer
Format: Article
Language:English
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Summary:Glioblastoma Multiforme (GBM) is the most aggressive form of primary brain tumor, with a median survival time of just 14 months. Although a number of targeted therapies have been devised for these tumors, they have proved to be ineffective due to the high degree of inherent heterogeneity exhibited by them. An alternative and more attractive strategy is to exploit their altered metabolism, a feature shared by virtually all tumor cells. This can be accomplished using the therapeutic ketogenic diet (KD) which is a high fat, very low carbohydrate and adequate protein diet. This changes metabolism by increasing blood ketone and decreasing blood glucose and is currently used for the clinical management of refractory paediatric epilepsy. Previous studies have shown the KD to extend survival in a number of animal models of glioma and potentiate the effects of radiotherapy in some of them. The addition of ketones to tumor cells in vitro mimics the effects seen in vivo. In an attempt to unravel the mechanistic basis behind these effects, we carried out small RNA sequencing of tumors from mice fed either a KD or standard diet (SD). Our results highlighted global upregulation of miRNAs with tumor suppressor function, typically downregulated in gliomas, in animals fed a KD verses those fed a SD. These include miR-138-1-5p, miR-204-5p and several members of the mmu-let-7 family members. Furthermore, we observed a corresponding downregulation of many of the target genes of these miRNAs in KD fed animals. These target genes have previously been shown to be important regulators of tumor growth and invasion as well as chemo and radio-resistance. Our results reveal that altering metabolism using the KD changes the epigenetic landscape of GBM tumors and effects the regulation of key genes critical for tumor survival.
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/nox168.395