Glioblastoma (GBM) remains among the deadliest tumour-types without suitable cure. The failure of all clinical trials in the past decade can be attributed to the extensive (epi)genetic and phenotypic heterogeneity within and across patients, and the presence of ‘plastic’ cancer stem-like cells that can easily adapt to therapeutic interventions. Radiation therapy (RT), a cornerstone of the current standard-of-care, was previously shown to fuel GBM tumour cell plasticity and drive resistance. The identification of suitable targets that can
interfere with GBM plasticity and radiation-induced resistance, could therefore improve the effectiveness of RT and as such increase the effectiveness of the current standard-of-care in patients. Here, we will subject a set of representative patient-derived GBM models to state-of-theart radiation modalities (photon and carbon-ion radiation). These samples
will then be subjected to extensive (spatial) single-cell multi-omics and their underlying regulatory programs will be characterized to identify druggable pathways to target radiation-induced resistance in a patient-tailored way.