Hypoxia in gliomas: a pathogenic driver and therapeutic opportunity

Gliomas are highly malignant brain tumours characterised by extensive areas of hypoxia which significantly contribute to therapy-resistance and reduced survival. Therapies that address the hypoxic microenvironment are therefore likely to significantly improve patient outcomes. Hypoxic regulation of Yes-associated protein (YAP) and its paralog TAZ – transcriptional co-activators whose increased activity enhance tumour survival – was investigated and observed to increase both YAP/TAZ expression and transactivation activity in glioma. Furthermore, YAP/TAZ were identified to be important for glutamine metabolism – an interesting finding since glutamine is heavily relied upon in hypoxic tumour cells to sustain anabolic growth. Suppressing YAP/TAZ activity could represent a novel means of targeting hypoxic gliomas and thus the effect of YAP inhibitor, verteporfin was investigated. Treatment of primary and immortalised glioma cell lines with verteporfin resulted in cell death but strikingly only under hypoxic conditions (1% O2). This investigation discovered that cell death occurs through a YAP-independent mechanism, predominately involving binding of free iron and production of reactive oxygen species. This results in disruption of normal cellular processes and death in cells already under oxidative stress – such as those in hypoxia. Overall, this study suggests that repurposing verteporfin represents a novel means of treating highly therapy-resistant, hypoxic cells in gliom