title: Poly (ADP-Ribose) polymerase inhibitor MK-4827 together with radiation as a novel therapy for metastatic neuroblastoma.
abstract: OBJECTIVE
  To assess poly (ADP-ribose) polymerase (PARP) inhibitor MK-4827 together with radiation for the treatment of neuroblastoma.
  
  
  METHODS
  Clonogenic survival assays were used to assess MK-4827, radiation and combination thereof in four neuroblastoma cell lines. In vivo efficacy was tested in a murine xenograft model of metastatic neuroblastoma. In vivo targeted inhibition and biological effects included measurement of cleaved caspase-3, γ-H2AX, and Ki 67 by immunohistochemistry (IHC) and poly-ADP-ribose by Enzyme-Linked Immunosorbent Assay.
  
  
  RESULTS
  Treatment of neuroblastoma cell lines reduced clonogenicity and resulted in additive effects with radiation. In vivo treatment with MK-4827 and radiation prolonged survival (p<0.01) compared to single modalities. In vivo superiority of MK-4827 plus radiation was further documented by significant elevations of cleaved caspase-3 and γ-H2AX in tumors from the combination group compared to single modality cohorts.
  
  
  CONCLUSIONS
  Combination of MK-4827 and radiation might provide effective therapy for children with high-risk neuroblastoma.
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Ring, Sandler Neuroscience Center, UCSF, San Francisco, CA 94148, USA. muellers@neuropeds.ucsf.edu
authors.forename: Sabine
authors.initials: S
authors.lastname: Mueller
authors.forename: Samhita
authors.initials: S
authors.lastname: Bhargava
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.forename: Ilan
authors.initials: I
authors.lastname: Kolkowitz
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Olow
authors.forename: Noor
authors.initials: N
authors.lastname: Wehmeijer
authors.forename: Sharon
authors.initials: S
authors.lastname: Orbach
authors.forename: Justin
authors.initials: J
authors.lastname: Chen
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006657:Histones / Q000032:analysis; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D051379:Mice; D009362:Neoplasm Metastasis; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D010880:Piperidines / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D007191:Indazoles; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; D053148:Caspase 3; C545685:niraparib