title: Targeting Wee1 for the treatment of pediatric high-grade gliomas.
abstract: BACKGROUND
  We investigated the efficacy of the Wee1 inhibitor MK-1775 in combination with radiation for the treatment of pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine gliomas (DIPGs).
  
  
  METHODS
  Gene expression analysis was performed for 38 primary pediatric gliomas (3 grade I, 10 grade II, 11 grade III, 14 grade IV) and 8 normal brain samples using the Agilent 4 × 44 K array. Clonogenic survival assays were carried out in pediatric and adult HGG cell lines (n = 6) to assess radiosensitizing effects of MK-1775. DNA repair capacity was evaluated by measuring protein levels of γ-H2AX, a marker of double strand DNA breaks. In vivo activity of MK-1775 with radiation was assessed in 2 distinct orthotopic engraftment models of pediatric HGG, including 1 derived from a genetically engineered mouse carrying a BRAF(V600E) mutation, and 1 xenograft model in which tumor cells were derived from a patient's DIPG.
  
  
  RESULTS
  Wee1 is overexpressed in pediatric HGGs, with increasing expression positively correlated with malignancy (P = .007 for grade III + IV vs I + II) and markedly high expression in DIPG. Combination treatment of MK-1775 and radiation reduced clonogenic survival and increased expression of γ-H2AX to a greater extent than achieved by radiation alone. Finally, combined MK-1775 and radiation conferred greater survival benefit to mice bearing engrafted, orthotopic HGG and DIPG tumors, compared with treatment with radiation alone (BRAF(V600E) model P = .0061 and DIPG brainstem model P = .0163).
  
  
  CONCLUSIONS
  Our results highlight MK-1775 as a promising new therapeutic agent for use in combination with radiation for the treatment of pediatric HGGs, including DIPG.
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California (S.M., I.K.); Department of Pediatrics, University of California, San Francisco, San Francisco, California (S.M., M.D.P., N.G.); Brain Tumor Research Center, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California (S.M., R.H., X.Y., A.K.O., J.P., M.W.T., C.D.J., M.S.B., N.G., D.A.H.-K.); Department of Neurological Surgery, University of California, San Francisco, San Francisco, California (S.M., J.P., I.S., M.D.P., C.D.J., M.S.B., N.G., D.A.H.-K.); Department of Radiation Oncology, University of California, San Francisco, San Francisco, California (D.A.H.-K.).
authors.forename: Sabine
authors.initials: S
authors.lastname: Mueller
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.forename: Ilan
authors.initials: I
authors.lastname: Kolkowitz
authors.forename: Aleksandra K
authors.initials: AK
authors.lastname: Olow
authors.forename: Joanna
authors.initials: J
authors.lastname: Phillips
authors.forename: Ivan
authors.initials: I
authors.lastname: Smirnov
authors.forename: Maxwell W
authors.initials: MW
authors.lastname: Tom
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Nalin
authors.initials: N
authors.lastname: Gupta
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D005909:Glioblastoma / Q000235:genetics / Q000628:therapy*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011744:Pyrimidinones
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib
keywords: MK-1775; Wee1 inhibition; diffuse intrinsic pontine glioma; pediatric high-grade glioma; radiation