Abstract 3271: Novel orthotopic pediatric high grade glioma xenografts evaluated with magnetic resonance imaging mimic human disease

Abstract

Abstract Pediatric high grade gliomas (pHGG) may arise supratentorially in the cerebral hemispheres, or in midline structures such as the thalamus or the pons (diffuse intrinsic pontine glioma, DIPG). Tumors have distinct underlying biology compared with adult disease, with genetic subtypes corresponding to anatomical location. Differential mutations in genes encoding histone H3.3/H3.1 variants occur in supratentorial and midline tumors, while mutations in the gene encoding the BMP type I receptor ACVR1 are restricted to the pons and occur in a quarter of DIPGs. Co-option of existing brain vasculature in areas of infiltrative tumor growth leaves the blood brain barrier (BBB) intact. It is imperative to accurately model these tumors in vivo for the evaluation of emerging targeted therapeutics. Assessment of such models in situ is vital and requires sensitive functional imaging. T2-weighted (T2-w) MRI of orthotopically implanted PBT7 cells (supratentorial glioblastoma (GBM), 9yr old, H3F3A wt) showed heterogeneous tumors with relatively well defined borders. Hypointensity on T2-w and fluid-attenuated inversion recovery (FLAIR) images suggests the presence of necrosis and edema. Minimal heterogenous enhancement following Gd-DTPA administration demonstrated some loss of BBB integrity. FLAIR hyperintensity is used clinically to identify infiltrative tumor. Serially xenografted D-212 MG cells (supratentorial giant-cell GBM, 11yr old, H3F3A wt) formed tumors with FLAIR hyperintensity principally at the rim and Gd-DTPA enhancement prevalent at the tumor core. Histopathological assessment of H&E staining confirmed the presence of masses with focal invasion at the periphery. Tumors established following pontine injection of HSJD-DIPG-007 cells (6yr old, H3F3A K27M, ACVR1 R206H) were identifiable by T2-w MRI hyperintensity in the pons and cerebellum. Histology confirmed a highly infiltrative tumor throughout the pons, cerebellum and leptomeninges, including the fissures of the cerebellum, which was validated by human nuclear antigen immunohistochemical staining. No extravasation of Gd-DTPA was observed indicating that the BBB remained intact. SU-DIPG-VI cells (6yr old, H3F3A K27M) grew diffusely in the pons with evidence of edema detected by T2-w MRI hyperintensity and FLAIR hypointensity. Diffusely hyperintense T2-w lesions with indistinct boundaries and limited Gd-DTPA extravasation were observed when imaging the diffusely infiltrative tumors resulting from thalamic implantation of QCTB-R059 primary thalamic GBM cells (10yr old, H3F3A K27M). In vivo propagation of primary and serially xenografted pHGG cells results in tumors that possess features of clinical disease, including infiltrative growth and necrosis. There is substantial potential for the use of these models to evaluate preclinical efficacy of novel therapeutics in a range of anatomical and biological subgroups of GBM and DIPG. Citation Format: Jessica K.R. Boult, Kathryn R. Taylor, Maria Vinci, Sergey Popov, Alexa Jury, Valeria Molinari, Marta M. Alonso, Wendy Ingram, Angel M. Caraboso, Michelle Monje, Suzanne A. Eccles, Chris Jones, Simon P. Robinson. Novel orthotopic pediatric high grade glioma xenografts evaluated with magnetic resonance imaging mimic human disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3271. doi:10.1158/1538-7445.AM2015-3271