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  3. A novel model of glioblastoma recurrence to identify therapeutic vulnerabilities

A novel model of glioblastoma recurrence to identify therapeutic vulnerabilities

  • EMBO Mol Med. 2025 Jun;17(6):1325-1354. doi: 10.1038/s44321-025-00237-z.
Sara Lucchini # 1,  James G Nicholson # 1,  Xinyu Zhang 1,  Jacob Househam 2,  Yau Mun Lim 3,  Maximilian Mossner 2,  Thomas O Millner 1 4,  Sebastian Brandner 3,  Trevor Graham 2,  Silvia Marino 5 6
Affiliations

Affiliations

  • 1 Brain Tumour Research Centre, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University London, London, UK.
  • 2 Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
  • 3 Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, and Department of Neurodegenerative Disease, Queen Square, Institute of Neurology, University College London, Queen Square, London, UK.
  • 4 Barts Brain Tumour Centre, Faculty of Medicine and Dentistry, Queen Mary University London, London, UK.
  • 5 Brain Tumour Research Centre, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University London, London, UK. s.marino@qmul.ac.uk.
  • 6 Barts Brain Tumour Centre, Faculty of Medicine and Dentistry, Queen Mary University London, London, UK. s.marino@qmul.ac.uk.
  • # Contributed equally.
PMID: 40295888 DOI: 10.1038/s44321-025-00237-z
Abstract

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.

Keywords

Cilia; Glioblastoma; Mouse Model; Precision-medicine; Recurrence.

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