DIPG-17. TELOMERE-INDUCED DAMAGE AS A NOVEL APPROACH TO TREAT DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract

AbstractDiffuse intrinsic pontine glioma (DIPG) is one of the deadliest brain tumors in children. Hence, there is an urgent need to identify actionable therapeutic targets. We have previously shown that over 70% of DIPGs demonstrate telomerase activity and elevated hTERT mRNA levels are associated with shorter overall survival. Thus, telomeres and telomerase represent ideal targets to treat DIPG. We recently validated a novel approach consisting of the incorporation of 6-thio-dG, a telomerase substrate analogue, into telomeres to treat therapy-resistant pediatric brain tumor cells. 6-thio-dG treatment of high-risk group 3 medulloblastoma, pediatric GBM and DIPG patients-derived neurospheres caused telomere damage leading to dose-dependent cell growth inhibition and complete abolition of sphere formation ability. Here, we present our results of the in vivo effectiveness of 6-thio-dG in orthotopic DIPG mouse models. Primary DIPG neurospheres were derived post-autopsy from patients’ tumor tissue. Luciferase positive cells were implanted in the pons of two strains of mice. The generated tumors were highly aggressive and the histopathological characterization of the xenograft showed close similarity with the original patient tumor. Relative to the original patient tissue and the derived neurospheres, telomerase expression and activity were sustained in the xenografts. Tumor bearing mice were treated with 6-thio-dG or the vehicle upon tumor establishment. Molecular analyses of the tumors showed that 6-thio-dG generated significantly higher number of telomere dysfunction-induced foci (TIFs) compared to the untreated tumors, indicating that 6-thio-dG reached the tumor tissue in the pons. Of note, 6-thio-dG treatment had no detectable effect on normal brain tissue. Results regarding tumor regression/stabilization and survival will be discussed. Our data suggest that 6-thio-dG-induced telomere damage is a promising novel approach to treat DIPG.