IMG-09. Characterisation of a panel ofin vivo models of paediatric-type diffuse high-grade glioma (PDHGG) using magnetic resonance imaging

Abstract

Novel therapies for paediatric-type diffuse high-grade glioma (PDHGG) are urgently required. Orthotopic models using patient-derived material are invaluable tools in preclinical drug development as they retain key genetic/epigenetic features, eg. histone H3G34 or H3K27 alterations. Their evaluation in situ is vital and requires sensitive imaging techniques such as MRI. 12 diffuse hemispheric glioma (DHG; 2 DHG-G34) and 21 diffuse midline glioma (DMG; 17 DMG-K27M) tumours have been characterised using MRI following site-specific orthotopic implantation of patient-derived cells directly from tumour material or after minimal expansion as stem cell cultures. Of the 62 models implanted; 3 DHG and 10 DMG samples were not tumourigenic and 13 DHG/3 DMG models are currently under MRI surveillance. Tumours identified on T2-weighted (T2w)-images varied from a diffuse hyperintense signal to well-defined high contrast masses. Tumour growth in 5 DMG models was too diffuse for longitudinal monitoring with T2w-MRI. Once established, diffusion-weighted, T1/T2 mapping and contrast-enhanced MRI were used to further assess tumour phenotype. Quantitative data from 15 DMG models demonstrated higher water diffusivity and T2 than 10 DHG tumours, which suggests less tightly packed tumour cells but may also reflect the closer proximity of tumours growing in the thalamus/pons/cerebellum to the ventricular system. Lack of contrast-agent enhancement in 11 DMG and 6/10 DHG models indicated an intact blood-brain barrier (BBB), with heterogeneous disruption observed in 4 DHGs; H3-G34 had no bearing on BBB integrity. Upon serial re-implantation survival was shortened in 3/4 DHG and 2/6 DMG models, while quantitative MRI parameters remained similar. Likewise, when 2 DHG and 2 DMG models grown in 2D/3D in vitro were implanted in parallel, poorer survival/improved penetrance was associated with 3D-cultured cells with no difference in imaging phenotype. The study highlights the potential of non-invasive MRI to accurately evaluate the efficacy of novel therapeutics in these PDHGG models.