Targeting H3K27-Altered Diffuse Midline Glioma with Combined MEK and HDAC Inhibition: Clinical Response and In Vitro Validation

Background/Objectives: Histone H3 K27-altered diffuse midline gliomas (DMGs) have poor outcomes and are characterized by global loss of H3K27 trimethylation (H3K27me3). Evidence from other H3K27me3-deficient tumors suggests a potential vulnerability to combined histone deacetylase (HDAC) and MEK inhibition. We examined a clinical experience with this combination and tested its activity in glioma models. Methods: We reviewed the course of an 11-year-old with neurofibromatosis type 1 and a thoracic spinal DMG treated with selumetinib and vorinostat after gross-total resection, without upfront radiotherapy. In post hoc viability assays, we tested HDAC and MEK inhibition in two H3K27M-mutant glioma lines, an isogenic K27-rescued derivative, and two H3-wildtype lines. Combination benefit was measured as the reduction in area under the viability curve relative to vorinostat alone. Results: The patient experienced 22 months of radiotherapy-free, progression-free survival before recurrence, with a postoperative enhancing focus resolving during treatment. Treatment was associated with grade 1 diarrhea and dermatitis. In vitro, combination benefit was greater in the H3K27M-mutant lines than in the H3-wildtype lines (mean difference, 13.2; 95% confidence interval, 8.1–18.3; p < 0.001). Benefit was also greater in DIPG17 than in its K27-rescued derivative (mean difference, 22.4; 95% confidence interval, 10.1–34.7; p = 0.015). Conclusions: This clinical observation and the post hoc validation experiments support prospective study of H3K27me3 loss as a candidate biomarker for combined HDAC and MEK inhibition.