DOI: 10.1007/s13311-017-0514-2 Pages: 274-283
Article Type: Review

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

1. University of Manitoba, Section of Pediatric Hematology/Oncology/BMT, CancerCare Manitoba, Research Institute in Oncology and Hematology, Departments of Pediatrics & Child Health and Biochemistry & Medical Genetics

2. University of Alberta, Division of Experimental Oncology, Department of Oncology, Cross Cancer Institute

3. University of Alberta, Division of Hematology/Oncology and Palliative Care, Stollery Children’s Hospital, Departments of Pediatrics, Medical Genetics and Oncology

Correspondence to:
David D. Eisenstat
Email: eisensta@ualberta.ca

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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.

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  • Online: Feb 23, 2017

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