BT-01TENASCIN-C: A NOVEL THERAPEUTIC TARGET IN PEDIATRIC BRAINSTEM GLIOMA

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is the most deadly solid tumor of childhood. Histone 3 mutation occurs in 80% of DIPGs, causing global transcriptional changes. Tenascin-C (TNC) is an extracellular matrix protein expressed during normal brain development by oligodendroglial progenitor cells (OPCs), the purported DIPG cell of origin. TNC is highly expressed in adult glioma, contributing to local invasion and poor survival. We report increased TNC in tumor tissue and cerebrospinal fluid (CSF) from children with high-grade glioma, including DIPG, and characterize TNC expression in relation to H3K27M mutation and DNA methylation status. METHODS: Tumor tissue collected intraoperatively or post-mortem from children with brainstem (DIPG, n = 14), supratentorial (n = 7), and cerebellar astrocytoma (n = 2), and CSF from DIPG (n = 9) and supratentorial astrocytoma (n = 17) was subjected to MS/MS proteomic analysis. Tissue gene expression, DNA methylation, H3F3A and HIST1H3B sequencing was performed. TNC expression was validated via Western blot and immunohistochemistry. Data integration was performed with Genome Studio, Partek and Ingenuity Pathway Analysis. RESULTS: TNC expression was significantly increased in 75% of gliomas compared to normal tissue, including all DIPG specimens tested (fold change >2, p < 0.05). Secreted TNC was detected in 7/9 DIPG CSF specimens (77.8%). Tumor-specific TNC expression was confirmed with Western blot and tissue immunohistochemistry. TNC expression correlated with tumor grade and was associated with Notch pathway activation, H3K27M mutation, and TNC promoter hypomethylation. CONCLUSIONS: We report increased TNC expression in tissue and CSF of pediatric high-grade gliomas, including DIPGs, associated with promoter hypomethylation and H3K27M mutation. Given the effect of TNC on OPC proliferation, migration and differentiation, TNC could serve as a clinical biomarker of disease and rational therapeutic target for a substantial subgroup of DIPG patients. Studies exploring the mechanism of TNC overexpression and effects of targeting TNC expression in DIPG are currently underway.