title: No Significant Cytotoxic Effect of the EZH2 Inhibitor Tazemetostat (EPZ-6438) on Pediatric Glioma Cells with Wildtype Histone 3 or Mutated Histone 3.3.
abstract: BACKGROUND
  Glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) belong to the most aggressive cancers in children with poor prognosis and limited therapeutic options. Therapeutic targeting of epigenetic proteins may offer new treatment options. Preclinical studies identified Enhancer of Zeste Homolog 2 (EZH2) within polycomb repressor complex 2 (PRC2) as a potential epigenetic anti-tumor target in adult GBM cells but similar inhibition studies in pediatric GBM/DIPG were still missing. Moreover, approximately 30% of pediatric high grade gliomas (pedHGG) including GBM and DIPG harbor a lysine 27 mutation (K27M) in histone 3.3 (H3.3) which is correlated with poor outcome and was shown to influence EZH2 function.
  
  
  METHODS
  The present study investigated the correlation of expression of EZH2 and other PRC2 genes (EZH1, SUZ12, EED) with overall survival of pediatric GBM patients and the cytotoxic impact of EZH2 inhibition by the novel agent Tazemetostat in pediatric GBM/DIPG cells harboring either a H3.3 mutation or a H3 wildtype.
  
  
  RESULTS
  EZH2 gene expression does not correlate with survival of pedHGG patients, and EZH2 inhibition does not induce significant cytotoxicity in pedHGG cells independently of H3.3 mutations.
  
  
  CONCLUSIONS
  We suggest that EZH2 inhibition might not offer an effective single agent treatment option for paedHGG patients. However, the therapeutic efficacy in combination with cytotoxic and/or other epigenetically active agents still has to be elucidated.
authors.affiliation: Department of Child and Adolescent Health/Division of Pediatric Hematology and Oncology, Universitatsklinikum Gottingen, Goettingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Department of Child and Adolescent Health/Division of Pediatric Hematology and Oncology, Universitatsklinikum Gottingen, Goettingen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Schill
authors.affiliation: Division of Pediatric Neurooncology, Heidelberg, Deutsches Krebsforschungszentrum, Baden-Württemberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Sturm
authors.affiliation: Division of Pediatric Neurooncology, Heidelberg, Deutsches Krebsforschungszentrum, Baden-Württemberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Pfister
authors.affiliation: Department of Pediatric Oncology and Hematology, VU medisch centrum School of Medical Sciences, Amsterdam, Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Hulleman
authors.affiliation: Clinic for General, Visceral, and Pediatric Surgery, Georg-August-Universitat Gottingen Universitatsmedizin, Gottingen, Germany.
authors.forename: S A
authors.initials: SA
authors.lastname: Johnsen
authors.affiliation: Department of Child and Adolescent Health/Division of Pediatric Hematology and Oncology, Universitatsklinikum Gottingen, Goettingen, Germany.
authors.forename: C M
authors.initials: CM
authors.lastname: Kramm
mesh_terms: D000293:Adolescent; D001549:Benzamides / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D005910:Glioma / Q000235:genetics* / Q000473:pathology*; D006657:Histones / Q000235:genetics*; D006801:Humans; D008297:Male; D009025:Morpholines; D011728:Pyridones / Q000494:pharmacology*; D013223:Statistics as Topic; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D055815:Young Adult
chemical_list: D001549:Benzamides; D001713:Biphenyl Compounds; D006657:Histones; D009025:Morpholines; D011728:Pyridones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C000593333:tazemetostat