# Adult-Onset Diffuse Midline Glioma, H3K27-Altered: A Genomics-Guided, Individualized, Multimodal Treatment Approach

## TL;DR

A personalized treatment combining genomic insights and multiple therapies significantly reduced tumor size in a patient with aggressive brain cancer.

## Contribution

Demonstrates a novel, genomics-guided multimodal treatment approach for H3K27-altered diffuse midline glioma.

## Key findings

- A personalized regimen achieved a 60% tumor volume reduction in a patient with H3K27-altered DMG.
- The treatment preserved neurological function with a Karnofsky Performance Score of 100%.
- Combining pathway inhibition, metabolic modulation, and electric field therapy showed clinical and radiological benefits.

## Abstract

Background: H3K27-altered diffuse midline glioma (DMG) is a highly aggressive central nervous system malignancy with limited therapeutic options and poor prognosis. Precision medicine strategies that integrate molecular profiling with individualized treatment selection represent a critical avenue for improving outcomes. Case presentation: We describe a 31-year-old woman with H3K27-altered DMG who, after standard chemoradiotherapy, was treated with a personalized, mechanism-guided combination regimen based on her tumor’s molecular profile. Next-generation sequencing identified pathogenic alterations in ATRX, H3F3A, and NF1, with a high NF1 mutation allelic fraction indicating RAS/MAPK pathway activation. Immunohistochemistry demonstrated elevated phosphorylated mTOR consistent with PI3K/AKT/mTOR pathway upregulation. The individualized regimen comprised trametinib and everolimus for dual pathway inhibition, the tissue-agnostic agent dordaviprone (ONC201), metabolic modulation with 2-deoxy-D-glucose, and electric field-based therapy. At seven months, MRI showed approximately a 60% volumetric reduction in the enhancing tumor component, accompanied by marked T2-weighted signal regression. Clinically, the patient remained neurologically intact with a Karnofsky Performance Score of 100%. Conclusions: This case illustrates the potential clinical value of a genomics-guided, multimodal treatment strategy in H3K27-altered DMG. The systematic integration of comprehensive molecular profiling with mechanistically rational treatment selection may contribute to meaningful radiological and clinical benefit in this otherwise uniformly fatal disease. These observations support further investigation of individualized, pathway-targeted approaches in prospective studies and N-of-1 trial frameworks.