Research And Grants

Exploiting Nucleolar Vulnerabilities in Paediatric High-Grade Gliomas

Aggressive brain cancers such as paediatric high-grade gliomas H3.3 and ATRX mutations are among the most challenging to treat, with limited options and poor outcomes. Recent discoveries, however, are opening promising new paths for targeted therapy.

Our research shows that mutations in key chromatin regulators—H3.3 and ATRX—not only drive tumour development but also create an unexpected vulnerability. These mutations disrupt regions of the genome called ribosomal DNA (rDNA), which produce RNA for building ribosomes—the cell’s protein factories. This disruption affects the nucleolus, a critical cell structure, and makes tumour cells unusually dependent on ribosome production.

This dependency offers a powerful opportunity for targeted treatment. We have shown that drugs blocking RNA Polymerase I (Pol I)—the enzyme responsible for rRNA synthesis—selectively impair tumour cells with these mutations while sparing healthy cells. Two such drugs, including a next-generation brain-penetrant compound, show strong promise in preclinical models.

Our project will uncover how H3.3 and ATRX mutations alter rDNA function and test Pol I inhibitors in advanced lab and animal models. By focusing on shared vulnerabilities, this work aims to deliver urgently needed, precision therapies for patients with currently untreatable brain cancers.