Neurotherapeutics

, Volume 14, Issue 2, pp 274–283 | Cite as

Targeting Epigenetic Pathways in the Treatment of Pediatric Diffuse (High Grade) Gliomas

Review

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.

Keywords

H3F3A HIST1H3B H3.3 K27M H3.1 K27M H3.3 G34R/V H3K27me (1, 2, 3) PDGFRA FGFR ACVR1 NTRK Epigenetic therapy 

Supplementary material

13311_2017_514_MOESM1_ESM.pdf (1002 kb)
ESM 1(PDF 1001 kb)
13311_2017_514_MOESM2_ESM.pdf (1.2 mb)
ESM 2(PDF 1224 kb)

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  1. 1.Section of Pediatric Hematology/Oncology/BMT, CancerCare Manitoba, Research Institute in Oncology and Hematology, Departments of Pediatrics & Child Health and Biochemistry & Medical GeneticsUniversity of ManitobaWinnipegCanada
  2. 2.Division of Experimental Oncology, Department of Oncology, Cross Cancer InstituteUniversity of AlbertaEdmontonCanada
  3. 3.Division of Hematology/Oncology and Palliative Care, Stollery Children’s Hospital, Departments of Pediatrics, Medical Genetics and OncologyUniversity of AlbertaEdmontonCanada

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