A Novel Orthotopic Patient-Derived Xenograft Model of Radiation-Induced Glioma Following Medulloblastoma.

Abstract

Simple SummaryRadiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy, for which there is currently no effective treatment. In order to test new drugs in the hope of finding more effective therapies, we need mouse models that faithfully replicate human RIG. Our laboratory collected tumour cells at autopsy from a paediatric patient with RIG following treatment for a different brain tumour. Using these cells, we created a mouse brain tumour model that retains all the characteristics and features of the original patient tumour from which it was derived. This unique model allowed us to study the progression of RIG in the brain, and to identify drugs that may be effective in the treatment of this disease. This mouse model will also allow us to test the efficacy of new treatments, with the hope of improving the prognosis for patients diagnosed with this disease.Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intrinsic pontine glioma (DIPG) based on disease location, results from methylation profiling and WGS were not consistent with this diagnosis. Furthermore, clustering analyses based on RNA expression suggested the tumours were distinct from primary DIPG. Additional gene expression analysis demonstrated concordance with a published RIG expression profile. Multiple genetic alterations that enhance PI3K/AKT and Ras/Raf/MEK/ERK signalling were discovered in TK-RIG915 including an activating mutation in PIK3CA, upregulation of PDGFRA and AKT2, inactivating mutations in NF1, and a gain-of-function mutation in PTPN11. Additionally, deletion of CDKN2A/B, increased IDH1 expression, and decreased ARID1A expression were observed. Detection of phosphorylated S6, 4EBP1 and ERK via immunohistochemistry confirmed PI3K pathway and ERK activation. Here, we report one of the first PDX models for RIG, which recapitulates the patient disease and is molecularly distinct from primary brain stem glioma. Genetic interrogation of this model has enabled the identification of potential therapeutic vulnerabilities in this currently incurable disease.