A consensus to accelerate drug development for DIPG/DMG

The Thirteenth Paediatric Strategy Forum focused on finding better treatments for children and young people with diffuse midline glioma (DMG), including DIPG. 

The event held in Toronto, Canada, last year was organised by ACCELERATE with collaboration from the European Medicines Agency (EMA), and support from the U.S. Food and Drug Administration (FDA).

Diffuse intrinsic pontine glioma (DIPG), develops in the pons region of the brain stem. A type of DMG, this group of tumours affect other midline regions, including the thalamus, brainstem and spine.

Paediatric Strategy Forum for

Diffuse Midline Gliomas in Children and Adolescents

"Paediatric Strategy Forums are multi-stakeholder meetings in which strategies regarding new drug development are discussed. Each Forum focuses on either a given paediatric malignancy or the development of a class of compounds with regards to their mechanism of action. These scientific meetings are aimed at facilitating prioritisation in order to better meet the needs of patients and to increase feasibility of paediatric developments" - Accelerate

The forum brought together researchers, doctors, patient advocacy groups, and representatives from ten pharmaceutical companies.

The participants aimed to identify the most promising targets, including single drugs and combinations in DMG, as well as a strategy for their development.

A number of therapeutic agents and their targets were discussed during the forum.

• Molecular/genetic targets

  • Based on extensive preclinical data, the most promising targets are PI3K, ACVR1, MAPK and PDGFRA mutations

• Metabolic Targets

  • Polyamine metabolism is elevated in DMG. DFMO and AMXT1501 combination showed promise but raised heart toxicity concerns, pausing paediatric trials.

  • Methionine metabolism is increased in DMG, and methionine restriction extended survival in animal models.

  
  

• Immunological Targets

  • The DMG microenvironment lacks immune cells and is characterised by immunosuppressive features. Oncolytic viruses are specially designed viruses that infect and kill cancer cells without hurting healthy ones. One oncolytic virus, the DNX-2401 stimulated immune responses in DMG. Early trials showed a median survival of 17.8 months in patients with previously untreated DIPG. A phase 2 trial is ongoing.

  • CAR-T cell therapy is a form of immunotherapy where a patient’s immune cells are modified to attack cancer. The GD2 and B7-H3 protein targets showed early promise with manageable side effects. More data are being collected.

  
  

• Epigenetic targets

  •  DMG cells depend on proteins like SMARCA4 and PRC2. Blocking them slowed tumour growth in lab models. PROTACs may help degrade these proteins. PROTACs (PROteolysis TArgeting Chimeras) are specialised drugs that encourage the body to break down harmful proteins.

    
    

• Cancer neuroscience targets

  • New research explores how nerve signals may support tumour growth. Blocking these signals or using CAR-T cells may offer new treatment paths.

    
    

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Tackling drug delivery

DMGs are protected by the blood-brain barrier, making drug delivery very difficult. Two promising methods that could help with delivering drugs directly to the tumour are being tested in animals and humans.

Convection Enhanced Delivery (CED) pumps medicine directly into the tumour, and Focused Ultrasound (FUS) which temporarily opens the blood-brain barrier to crucially allow drugs through.

Key Takeaways

There are a number of key recommendations that conclude the current inadequacy of the 'traditional model of pre-clinical investigation' - a summary of the key findings and the targets and drugs/drug combinations that are being tested in clinical trials.are discussed.

Conclusion

With the dismal prognosis of DMG it is absolutely vital for the DMG community to work together, swiftly and strategically to co-ordinate a new phase of biologically and clinically relevant clinical trials. International trials network groups such as PNOC, CONNECT, ITCC and new collaborations can achieve success by uniting in their expertise against the unmet need for new therapies and new trial designs.

Reference

Paediatric strategy forum for medicinal product development in diffuse midline gliomas in children and adolescents ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration

Andrew J Pearson et al

European Journal of Cancer, February 2025, volume 217, article 115230

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