Pediatric high-grade gliomas (pHGG) have proven to be extremely difficult to treat with a dismal survival rate. Fresh, innovative therapeutic approaches are desperately needed to combat this devastating disease. Hypomethylated Induced Target Mediated Apoptosis (HITMA), is a therapeutic strategy that targets and induces apoptosis only in cells that show an aberrant DNA methylation phenotype at repetitive sequences. Aberrant global DNA methylation is a hallmark of some pHGGs; however, the methylation status of repetitive sequences hasn’t been carefully evaluated. The first goal of this proposal is to thoroughly evaluate the methylation status of repetitive elements in different pHGG subtypes. Based on this, the second goal is to identify and generate an optimal HITMA strategy that will attack select subclasses of pHGG while sparing normal neural cell types. Therefore, if our HITMA-based strategy in pHGG is successful, we expect it to transform patient-specific therapeutic strategies in pHGG.