title: Targeting Epigenetic Pathways in the Treatment of Pediatric Diffuse (High Grade) Gliomas.
abstract: Progress in the treatment of adult high-grade gliomas (HGG), including chemoradiation with concurrent and adjuvant temozolomide for glioblastoma, has not translated into significant therapeutic advances for pediatric HGG, where overall survival has plateaued at 15% to 20%, especially when considering specialized pediatric treatment in tertiary care centers, maximal safe neurosurgical resection, optimized delivery of involved field radiation, and improvements in supportive care. However, recent advances in our understanding of pediatric HGG, including the application of next-generation sequencing and DNA methylation profiling, have identified mutations in the histone variant H3.3 and canonical H3.1 genes, respectively. These mutations are relatively specific to neuroanatomic compartments (cortex, midline structures, thalamus, brainstem) and are often associated with other mutations, especially in specific growth factor receptor tyrosine kinases. Targeting epigenetic pathways affected by these histone mutations, alone or in combination with small molecule inhibitors of growth factor receptor signaling pathways, will inform new treatment strategies for pediatric HGG and should be incorporated into novel cooperative group clinical trial designs.
authors.affiliation: Section of Pediatric Hematology/Oncology/BMT, CancerCare Manitoba, Research Institute in Oncology and Hematology, Departments of Pediatrics & Child Health and Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB, Canada. mivanan@cancercare.mb.ca.
authors.forename: Magimairajan Issai
authors.initials: MI
authors.lastname: Vanan
authors.affiliation: Division of Experimental Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: D Alan
authors.initials: DA
authors.lastname: Underhill
authors.affiliation: Division of Hematology/Oncology and Palliative Care, Stollery Children's Hospital, Departments of Pediatrics, Medical Genetics and Oncology, University of Alberta, Edmonton, AB, Canada. eisensta@ualberta.ca.
authors.forename: David D
authors.initials: DD
authors.lastname: Eisenstat
mesh_terms: D000293:Adolescent; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D060787:Neoplasm Grading
chemical_list: D006657:Histones
keywords: ACVR1; Epigenetic therapy; FGFR; H3.1 K27M; H3.3 G34R/V; H3.3 K27M; H3F3A; H3K27me (1, 2, 3); HIST1H3B; NTRK; PDGFRA