Search

Fewer than 10 % of children with diffuse midline glioma (DMG) survive 2 years from diagnosis. Radiation therapy remains the cornerstone of treatment and there are no medicinal products with regulatory approval. Although the biology of DMG is better characterized, this has not yet translated into effective treatments. H3K27 -alterations initiate the disease but additional drivers are required for malignant growth. Hence, there is an urgent unmet need to develop new multi-modality therapeutic strategies, including alternative methods of drug delivery. ONC201 (DRD2 antagonist and mitochondrial ClpP agonist) is the most widely evaluated investigational drug. Encouraging early data is emerging for CAR T-cells and oncolytic viruses. GD2, B7-H3 and PI3K signalling are ubiquitous targets across all subtypes and therapeutics directed to these targets would potentially benefit the largest number of children. PI3K, ACVR1, MAPK and PDGFRA pathways should be targeted in rational biological combinations. Drug discovery is a very high priority. New specific and potent epigenetic modifiers (PROTACS e.g. SMARCA4 degraders), with blood-brain penetrance are needed. Cancer neuroscience therapeutics are in early development. Overall survival is the preferred regulatory endpoint. However, the evaluation of this can be influenced by the use of re-irradiation at the time of progression. An efficient clinical trial design fit for regulatory purposes for the evaluation of new therapeutics would aid industry and facilitate more efficient therapy development. Challenges in conducting clinical trials such as the need for comparator data and defining endpoints, could be addressed through an international, first-in-child, randomised, complex innovative design trial. To achieve progress: i) drug discovery; ii) new multi-modality, efficient, collaborative, pre-clinical approaches, possibly including artificial intelligence and, iii) efficient clinical trial designs fit for regulatory purposes are required. • Less than 10 % of children with DMG survive beyond 2 years from diagnosis • GD2, B7-H3 and PI3K/mTOR signalling are ubiquitous targets for all subtypes of DMG • Encouraging early data is emerging for CAR T-cells and oncolytic viruses • Drug discovery is a high priority for epigenetic modifiers e.g. SMARCA4 degraders • An international, randomised, platform, complex innovative design trial is a goal [ABSTRACT FROM AUTHOR]