Molecular Horizons Seminar - Professor Matt Dun

Diffuse midline gliomas (DMGs), including those diagnosed in the pons of the brainstem (diffuse intrinsic pontine glioma - DIPG), are paediatric central nervous system tumours recognised as the most lethal of all children’s cancers. Palliative radiotherapy remains the only approved treatment, with survival just 9-11 months post-diagnosis. DIPG is responsible for more deaths from cancer than any other childhood malignancy.

The small molecule brain-penetrant drug, dordaviprone (ONC201), shows preclinical and emerging clinical efficacy in early-stage clinical trials and expanded accesses schemes, which represents the first improvements in DIPG/DMG survival outcomes in >60 years of research. However, patients still succumb within 2-years of diagnosis. Using a systems biological approach, Prof Dun’s team identified the mechanism of action dordaviprone in DIPG and identified mechanisms of therapeutic escape through redox regulated oncogenic PI3K/Akt/mTOR signalling. These data and DIPG patient case study data now underpins the world’s largest international DIPG clinical trial (NCT05009992) that is open in 36 hospitals worldwide, with >100 children currently enrolled. The trial is testing radiotherapy in combination with dordaviprone and the PI3K/mTOR inhibitor paxalisib that was discovered for the treatment of DIPG by Prof Dun in 2018. Early clinical results from this combination show dramatic reductions in tumour volumes, extending overall survival for the first two Australian patients, now 30- and 31-months post diagnosis (continuing), effectively trebling survival.