Diffuse Midline Gliomas: Clinical, Diagnostic, and Therapeutic Perspectives

Area of Science:

• Neuro-oncology
• Molecular Pathology
• Cancer Biology

Background:

• Diffuse midline gliomas (DMGs) are rare, aggressive central nervous system (CNS) tumors affecting pediatric and adult populations.
• Redefined in 2016 and updated in 2021 (WHO), DMGs are now classified as H3 K27-altered, encompassing H3 K27M mutations and other drivers.
• These WHO grade 4 tumors infiltrate midline structures, posing diagnostic and therapeutic challenges due to location and aggressive nature.

Purpose of the Study:

• To provide a comprehensive review of diffuse midline gliomas (DMGs).
• To discuss recent advancements in DMG biology and the evolving therapeutic landscape.
• To highlight opportunities for future research and treatment development.

Main Methods:

• Review of integrated histopathological and molecular features for DMG classification.
• Analysis of clinical presentation, neuroimaging, and diagnostic confirmation methods.
• Examination of current treatment modalities including radiation therapy, chemotherapy, and novel approaches.

Main Results:

• Surgical resection is often infeasible due to tumor location.
• Radiation therapy is a primary treatment, but chemotherapy lacks durable efficacy.
• Dordaviprone (ONC201) received accelerated FDA approval as the first systemic therapy for progressive H3 K27M-mutant DMG.

Conclusions:

• DMGs are formidable tumors requiring multidisciplinary management.
• The approval of dordaviprone marks a significant therapeutic breakthrough.
• Ongoing investigations into CAR T-cell therapies and convection-enhanced delivery show promise for future treatment strategies.