A novel model of glioblastoma recurrence to identify therapeutic vulnerabilities.

Glioblastoma remains incurable and recurs in all patients. Here we design and characterize a novel induced-recurrence model in which mice xenografted with primary patient-derived glioma initiating/stem cells (GIC) are treated with a therapeutic regimen closely recapitulating patient standard of care, followed by monitoring until tumours recur (induced recurrence patient-derived xenografts, IR-PDX). By tracking in vivo tumour growth, we confirm the patient specificity and initial efficacy of treatment prior to recurrence. Availability of longitudinally matched pairs of primary and recurrent GIC enabled patient-specific evaluation of the fidelity with which the model recapitulated phenotypes associated with the true recurrence. Through comprehensive multi-omic analyses, we show that the IR-PDX model recapitulates aspects of genomic, epigenetic, and transcriptional state heterogeneity upon recurrence in a patient-specific manner. The accuracy of the IR-PDX enabled both novel biological insights, including the positive association between glioblastoma recurrence and levels of ciliated neural stem cell-like tumour cells, and the identification of druggable patient-specific therapeutic vulnerabilities. This proof-of-concept study opens the possibility for prospective precision medicine approaches to identify target-drug candidates for treatment at glioblastoma recurrence.