title: Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma.
abstract: Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT (facilitates chromatin transcription) as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small-molecule curaxin compound CBL0137 markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma.
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. School of Women's and Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carter
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Jayne
authors.initials: J
authors.lastname: Murray
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. School of Women's and Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia.
authors.forename: Belamy B
authors.initials: BB
authors.lastname: Cheung
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Gamble
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Koach
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Joanna
authors.initials: J
authors.lastname: Tsang
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Selina
authors.initials: S
authors.lastname: Sutton
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Heyam
authors.initials: H
authors.lastname: Kalla
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Syed
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. Department of Anatomical Pathology (SEALS), Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gifford
authors.affiliation: Department of Surgery, Otolaryngology, and Yale Cancer Center, Yale University, New Haven, CT 06511, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Issaeva
authors.affiliation: Department of Surgery, Otolaryngology, and Yale Cancer Center, Yale University, New Haven, CT 06511, USA.
authors.forename: Asel
authors.initials: A
authors.lastname: Biktasova
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Bernard
authors.initials: B
authors.lastname: Atmadibrata
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sokolowski
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Dora
authors.initials: D
authors.lastname: Ling
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Kim
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Hannah
authors.initials: H
authors.lastname: Webber
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Clark
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Ruhle
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, 50931 Cologne, Germany. Department of Neonatology and Pediatric Intensive Care Medicine, Children's Hospital, University of Cologne, 50931 Cologne, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Oberthuer
authors.affiliation: Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, 50931 Cologne, Germany. Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia. University of Sydney Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Byrne
authors.affiliation: Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia.
authors.forename: Federica
authors.initials: F
authors.lastname: Saletta
authors.affiliation: Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia. University of Sydney Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia.
authors.forename: Le Myo
authors.initials: le M
authors.lastname: Thwe
authors.affiliation: Incuron, LLC, Buffalo, NY 14203, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Purmal
authors.affiliation: Buffalo BioLabs, LLC, Buffalo, NY 14203, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Haderski
authors.affiliation: Buffalo BioLabs, LLC, Buffalo, NY 14203, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Burkhart
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Beckers
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. School of Women's and Children's Health, UNSW Australia, Randwick, New South Wales 2031, Australia. Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales 2031, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Ziegler
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Incuron, LLC, Buffalo, NY 14203, USA. Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Katerina V
authors.initials: KV
authors.lastname: Gurova
authors.affiliation: Incuron, LLC, Buffalo, NY 14203, USA. Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. University of New South Wales Centre for Childhood Cancer Research, Randwick, New South Wales 2031, Australia.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. g.marshall@unsw.edu.au mhaber@ccia.unsw.edu.au.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia. Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales 2031, Australia. g.marshall@unsw.edu.au mhaber@ccia.unsw.edu.au.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009423:Nervous System Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D035602:Transcriptional Elongation Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000600493:CBLC137; D002227:Carbazoles; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C073537:SSRP1 protein, human; D035602:Transcriptional Elongation Factors