Abstract 3072: Clinically relevant MAPK pathway inhibition reverses stem cell fate defects and sensitize BRAF mutant glioma to immune modulatory therapies

Abstract

Pediatric low-grade gliomas (pLGG) are the most common central nervous system (CNS) tumor in children. Although the majority of pLGG has unregulated MAPK pathway activity, and clinical MAPK pathway inhibitors are available, pLGG treatment remains challenging. Tumor progression, rebound, and therapy resistance limit the success of MAPK pathway inhibitors, especially in high risk subgroups, such as BRAF V600E mutant CDKN2A deleted gliomas.To define mechanisms for progression and overcome resistance, we generated BRAF V600E mutant, CDKN2A deleted murine glioma models of different grades and drug sensitivities. Here, we use genetically engineered mice to target expression of BRAF V600E and deletion of CDKN2A to various germinal and non-germinal areas, assessing neuro-anatomical aspects of oncogene sensitivity. Using neural stem cell (NSC)- and astrocyte-, and oligodendrocyte progenitor cell (OPC)-selective driver line, we investigate the likely origin for pLGG and therapy resistant glioma stem cells, developing models that faithfully recapitulate human tumor development. Our numerous immunocompetent, orthotopic BRAF V600E mutant glioma model derived from endogenous tumors exhibit a range of sensitivities to MAPK inhibitor therapies, allowing us to define mechanisms for therapy resistance. In syngeneic, orthotopic BRAF V600E mutant CDKN2A deleted gliomas, we define MAPK pathway inhibitor-induced-changes in the tumor microenvironment, including the immune infiltrate, and investigate immune modulatory therapy as novel treatment strategy for children with BRAF mutant gliomas. Our numerous models for BRAF mutant glioma will facilitate research on tumor development, progression and the tumor-immune interactions. Collectively, our results describe genetic alteration- and microenvironment-based mechanisms for BRAF mutant tumor initiation and progression, and suggest therapeutic combination therapies for glioma. Citation Format: Claudia K. Petritsch, Stefan Grossauer, Wei Wang, Anne Marie Barrette, Jongwhi Park. Clinically relevant MAPK pathway inhibition reverses stem cell fate defects and sensitize BRAF mutant glioma to immune modulatory therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3072.