BT-09: TRILEXIUM INHIBITS THE EXPRESSION OF t-NOX AND IS A NOVEL, POTENTIALLY POTENT THERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMAS

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a surgically incurable pediatric brain tumour for which no effective treatment has been developed. Benzopyrans are a novel anti-cancer therapy that can initiate several mechanisms of cell death via several pathways including inhibition of tumor-associated NOX (t-NOX). Trilexium is a derivative of simple benzopyrans and is expected to cross the blood brain barrier. We have shown that DIPG cells are sensitive to other agents that inhibit cellular metabolism and we therefore investigated whether Trilexium may represent a novel and effective therapy for DIPG. METHODS: Expression of t-NOX was measured using Western blot in DIPG neurospheres, healthy lung fibroblasts, and normal human astrocytes. Western blots were also used to evaluate the effect of trilexium on t-NOX expression and its mechanism of action. RESULTS: t-NOX expression was observed in DIPG neurospheres and was undetected in normal human astrocytes and fibroblasts. Trilexium inhibited viability across a panel of four independent DIPG patient derived neurospheres in short term culture at nanomolar concentrations, but was ineffective against control non-malignant cells. We found that Trilexium exerts its anti-proliferative effect through the induction of apoptosis with marked increases the levels of cleaved caspase 3 and caspase 8, as well as cleaved PARP following short term treatment. Further, Trilexium suppresses the expression of AKT protein while enhances the phosphorylated p53. CONCLUSION: Our findings indicate that targeting t-NOX with trilexium represents a novel, potentially effective therapy for children with DIPG.