HG-24: GLUCOCORTICOID-MEDIATED EPIGENOMIC REVERSAL IN DIFFUSE INTRINSIC PONTINE GLIOMAS

Approximately 80% of diffuse intrinsic pontine glioma (DIPG) patients harbor mutations in the histone H3 genes which drive tumorigenesis by inducing global hypomethylation. Glucocorticoids are known to affect the epigenetic landscape of cells in various diseases. Therefore, the objective of this study is to determine the effects of glucocorticoid treatment on restoring epigenetic patterns of DIPG. Dexamethasone, a glucocorticoid routinely used to treat symptoms of peritumoral edema in DIPG patients and/or vamorolone, a novel dissociative steroidal analogue, were used to treat in vitro and in vivo DIPG tumor models that carried histone mutations. Human primary DIPG cells were treated with steroids, followed by assessments of DNA methylation, gene expression and histone trimethylation. For in vivo studies, histone trimethylation status and survival were evaluated on tumor bearing mice. In vitro exposure of DIPG cells to glucocorticoids resulted in reversed DNA methylation patterns from a hypo- to a hyper- methylated state, and decreased expression of genes associated with gliomagenesis and proliferation. Results of both models indicate no significant changes in histone trimethylation as a result of steroid treatments. However, a longer treatment regimen may be required for effective restoration of ‘normal’ epigenome with respect to histone trimethylation. Additionally, our data indicated that the treatment with vamorolone resulted in a more stringent reversal of epigenetic patterns, in vitro, and increased survival of DIPG mice. Further investigation of the mechanism which leads to the restoration of methylation patterns of H3 mutant cells could prove to be a promising therapeutic avenue for treating DIPG.