HG-06 * INHIBITION OF EPIGENETIC REGULATION AS A THERAPY FOR PEDIATRIC HIGH GRADE GLIOMA

Abstract

Pediatric high grade glioma (HGG), which ranks among the most lethal of cancers among children, contain two recurrent mutations within the histone H3.3 gene H3F3A (K27M and G34R/V). Recent studies have now shown H3 K27M mutations have specific alterations in methylation of endogenous histone H3 at Lys27 and global reduction of H3K7me3 on chromatin suggesting these mutations are directly linked to epigenetic regulation. It is not clear whether specific epigenetic regulatory mechanisms may be involved in H3K27M-tumor proliferation and growth, and contributes to their therapeutic resistance and rapid recurrence, or is common among wild-type pediatric HGG. Our investigation focused on distinguishing H3 K27M from wild-type (non-H3.3 mutation) tumors based on cellular hierarchy and pharmacotherapies targeting histone deacetylase (HDAC) and methyltransferase (HMT), p53 and bromodomain mechanisms to disrupt tumor growth and survival. Preliminary results from our lab (90 epigenetic compounds tested) have identified more than twenty effective drugs that killed or altered proliferation and growth in five pediatric HGG in vitro which had no adverse effect on non-neoplastic “normal” cells. Top candidates, which included 3 HMT and 17 HDAC inhibitors, did not preferentially affect tumors with H3 K27M mutation. It was noted that broad HMTi had greater effectiveness than more specific ones suggesting the influence of global methylation on survival. We are validating these findings in additional HGG cell lines and through in vivo studies, and determining whether other co-mutations exist. Additional studies are ongoing to identify specific epigenetic mechanisms that are unique to pediatric HGG with H3 K27M mutation or which may increase sensitization to current radio- and chemotherapy ultimately leading to improve patient outcome.