Targeting the DNA damage response for treatment of pediatric glioblastoma

High-grade glioma such as glioblastoma are not always equal in children and adults. In pediatric patients, the tumor location, cell type, treatment and prognosis differ from that of adults, arising through distinctly different genomic and epigenomic drivers of disease. In both the pediatric and adult setting, there are currently no effective therapies to fight glioblastoma. Following surgery, frontline adjuvant therapies consisting ofradiation and alkylating agents relyon DNA damage and requisite cellular responses to only temporarily reduce tumor burden.Emerging evidence suggest therapies targeting the DNA damage response (DDR)that is activated by DNA damaging chemotherapy and/or radiation may demonstrate improved efficacy in a frontline or recurrent setting. As we improve our understanding of the mechanisms underlying the DDR in brain tumors, identifyingoptimal strategies to override DNA repair with cell death is central to overcoming therapeutic resistance observed in childhood brain tumors. This review summarizes clinical challenges facing pediatricglioblastoma patients,and highlights opportunities to exploit DNA damage and replicative stress through the integration of conventional chemotherapy withtargeted DDR inhibition