ID #815 Targeting dopamine receptor signalling and mitochondrial metabolism as a therapeutic approach for diffuse midline gliomas

Abstract

Diffuse midline glioma (DMG) is a highly aggressive paediatric brain tumour with a very poor prognosis, and survival outcomes have remained largely unchanged despite ongoing research efforts. One important biological feature of many solid tumours is hypoxia, a condition characterised by reduced oxygen availability within the tumour microenvironment. Hypoxia can influence tumour behaviour and may limit the effectiveness of standard treatments such as chemotherapy and radiotherapy, which rely in part on oxygen-dependent mechanisms to induce tumour cell damage.

Our recent work suggests that hypoxia is present in DMG tumours and indicates that targeting mitochondrial metabolism may help reduce tumour oxygen consumption and improve responsiveness to radiotherapy. Using phenformin, an anti-diabetic drug, we demonstrated suppression of mitochondrial respiration in DMG cells alongside enhanced treatment sensitivity. However, phenformin is not suitable for clinical use due to safety concerns, highlighting the need to identify safer and more clinically applicable alternatives.

To address this, we conducted a large-scale screen of FDA-approved drugs and identified several promising candidates with mitochondrial inhibitory properties. These compounds reduced oxygen consumption, showed anti-DMG activity, and enhanced radiosensitivity in preclinical models. Notably, the leading candidates also modulate dopamine receptor signalling pathways and have demonstrated anti-cancer activity in multiple preclinical systems. This dual targeting of dopamine signalling and mitochondrial metabolism mirrors the mechanism of action of ONC201, a leading therapeutic candidate for DMG currently in phase III clinical trials.

Collectively, these findings suggest that targeting dopamine receptor signalling alongside mitochondrial metabolism represents a promising strategy to inhibit tumour growth and enhance radiotherapy efficacy in DMG. Ongoing studies aim to further define the underlying mechanisms, validate efficacy in preclinical DMG models, and optimise therapeutic approaches to support future clinical translation.