Abstract A47: Inhibition of histone methyltransferase with novel epipolythiodioxopiperazines (ETP) alkaloids in pediatric high-grade glioma
Dombrowski, S; Abou-Antoun, T; Mansour, A; Arar, R; Movassaghi, M; Murphy, E; Banerjee, S; Li, X-N; Houghton, P; Bigner, D; Carcaboso, AM ...
Published in: Cancer Research
Pediatric high-grade glioma (HGG), which ranks among the most lethal of cancers among children, contain two recurrent mutations within the histone H3 gene H3F3A (K27M and G34R/V). It is not known whether these mutations directly alter specific epigenetic regulatory mechanisms that may be involved in tumor proliferation and growth, or contribute to their therapeutic resistance and rapid recurrence. Preliminary findings from our lab have identified that Chaetocin (CH), a pan histone methyltransferase (HMT) inhibitor, and two newly synthesized epipolythiodioxopiperazines (ETP) alkaloids that are structurally and functionally distinct HMT inhibitors can effectively kill pediatric HGG (N=7), including three that contain the H3 K27M mutation. In addition, CH and ETPs can also inhibit tumor sphere formation and cell migration at low concentrations (<0.5uM) through in vitro studies. In H3 K27M tumors, these HMTi were shown to reverse hypomethylation of K27me3 transiently (<48 hours). We also found these HMTis to decrease tumor stem cell expression (Sox2, Oct4), and increase tumor-suppressor activity (PTEN, p53) for three pediatric HGG up to 72 hours. These results suggest ETP effectiveness that acts through direct HMT inhibition may also influence other tumorigenic pathways, which may in part contribute to their aggressive nature. Results from this investigation have advanced our understanding of epigenetic regulation of solid brain tumors, and identified drugs that may specifically target pediatric H3 K27M tumor subtypes and could ultimately improve overall survival in pediatric patients with high-grade glioma.Citation Format: Stephen Dombrowski, Thamara Abou-Antoun, Anthony Mansour, Rewa Arar, Mohammad Movassaghi, Erin Murphy, Shuvojit Banerjee, Xiao-Nan Li, Peter Houghton, Darell Bigner, Angel Montero Carcaboso, Jeremy Rich, Violette Recinos. Inhibition of histone methyltransferase with novel epipolythiodioxopiperazines (ETP) alkaloids in pediatric high-grade glioma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A47.