NFB-20. Pre-clinical models of Mismatch Repair Deficient Gliomas

Abstract

INTRODUCTION: Lynch syndrome and Biallelic Mismatch Repair Deficiency (BMMRD) are hereditary tumor predisposition syndromes, resulting from one or two (respectively) germline alterations in DNA mis-match repair (MMR) genes. Currently, there are few treatments for mismatch repair deficient (MMRD) gliomas, in part due to a lack of suitable pre-clinical models for drug testing. The purpose of this study is to develop and characterize pre-clinical models of MMRD gliomas. METHODS: Primary cells were developed from patients diagnosed with MMRD gliomas and characterized through immunofluorescence staining (IF) for different cell type markers, western blot assays, and genome and transcriptome analysis. Murine models were generated through intracranial injection of mCherry-luciferase reporter expressing primary cells, and mice were monitored for evidence of engraftment and clinical symptoms. Drug screening on the cell lines was performed to identify potential therapeutic agents for in-vivo testing. RESULTS: The cell lines had similar characteristics as the primary glial tumors by IF staining and genome and transcriptome analysis. Adult NSG mice developed tumors around three weeks after intercranial transplantation of the tumor cells. These tumors closely resembled the primary patient tumors on histology. Preliminary drug testing on the cell lines showed efficacy of ONC201, ONC206, and RM006 against MMRD gliomas with IC50 concentrations of 1.77 μM, 185 nM, and 699 nM respectively. CONCLUSION: The generation of pre-clinical MMRD glioma models can lead to improved understanding of tumorigenesis, allowing for the identification of targetable molecules, and supporting novel treatment development.