EPND-12. TYROSINE KINASE INHIBITORS AXITINIB, IMATINIB AND PAZOPANIB ARE SELECTIVELY POTENT IN EPENDYMOMA

Abstract

s iv17 NEURO-ONCOLOGY • JUNE 2017 and exhibited clinical features consistent with previously described PFA subgroup of ependymomas. Together these data suggest that the epigenet-ics of the developing posterior fossa are closely related to the pathogenesis of childhood brain tumors and have clinical implications for biomarker development and to inform epigenetic approaches to treat PF ependymo-mas. Recent deep molecular analyses of Ependymomas (EPNs) have revealed that supratentorial ependymomas (ST-EPNs) consisted of two different molecular subgroups denoted as ST-EPN-YAP1 and-RELA which associates with YAP1-and RELA-involved fusion gene, respectively. These fusion genes may provide significant and distinct therapeutic insights for each EPN subtypes. ST-EPN-RELA subgroup associates with C11orf95-RELA fusion gene (CR). The presence of RELA as one component of the CR leads to the suggestion that NF-kB activity may be essential for onco-genesis and a viable therapeutic target in these tumors. So far, we have demonstrated that the CR was a potent oncogene which was capable of inducing human EPN-like tumor in mice. However it still remains to be cleared whether NF-kB/RelA activity involved in the CR-induced tumor formation. Therefore, we undertook an extensive analysis of the connection between NF-kB/RelA activity and oncogenesis for the CR. We created various CR mutants with modification(s) in phosphorylation or acetyla-tion site of RelA portion and tested their oncogenic potential in mice. These mutants presented superior or inferior tumor forming potential than the CR. When NF-kB/RelA activity of these mutants was measured with luciferase reporter assay in cultured fibroblasts, prominent NF-kB activity was not observed in any CR mutants and there was no correlation between NF-kB/RelA activity and tumor forming potential. Further when NF-kB activity of these CR mutants was examined using cultured fibroblasts and mouse tumors in RNA-seq, minimal NF-kB activity was observed in these mutants but not correlated with their tumor forming potential as well. These results suggested that NF-kB/RelA activity is unlikely essential for the process of tumor initiation in the CR-induced EPN formation, and the oncogenic effect of CR mostly derives from factor other than NF-kB activation. Therefore we will need further elaborate investigation whether NF-kB/RelA pathway is a right therapeutic target for these tumors.