DIPG-09. HDAC INHIBITION IN THALAMIC AND SPINAL CORD H3K27M+ DIFFUSE MIDLINE GLIOMA

Abstract

BACKGROUND

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of brain tumor-related deaths in children. There are no effective treatments and median survival remains dismal. Genomics identified a mutation in the majority of DMGs, a lysine to methionine substitution (K27M) in histones 3.1 and 3.3, which causes changes in gene expression that promote gliomagenesis. Panobinostat, a multiple histone deacetylase (HDAC) inhibitor, was one of the most effective agents against patient-derived DIPG cell cultures and xenograft models in previous studies and is presently in clinical trial for DIPG. HDAC inhibition with panobinostat may also exhibit activity against H3K27M+ DMG of the thalamus and spinal cord.

METHODS

Patient-derived thalamic and spinal cord H3K27M+ DMG cell cultures were treated with single agent panobinostat at a range of concentrations. Cell viability was evaluated using the CellTiter-Glo assay. Panobinostat was systemically administered to murine models of luciferase-expressing spinal cord H3K27M+ DMG. Response to panobinostat was evaluated with IVIS in vivo imaging.

RESULTS

HDAC inhibition with panobinostat significantly decreases cell proliferation with an IC50 of 30 nM and 41 nM in the spinal cord and thalamic glioma patient-derived cell cultures respectively. Panobinostat slowed tumor growth in spinal cord glioma orthotopic xenografts compared to vehicle controls.

CONCLUSION

This study suggests that HDAC inhibition with panobinostat may also be beneficial for thalamic and spinal cord H3K27M+ DMG.