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Sci Transl Med. 2015 Nov 4;7(312):312ra176. doi: 10.1126/scitranslmed.aab1803.

Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma.

Author information

1
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.
2
Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
3
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.
4
Department of Surgery, Otolaryngology, and Yale Cancer Center, Yale University, New Haven, CT 06511, USA.
5
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.
6
Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, 50931 Cologne, Germany. Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.
7
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.
8
Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia.
9
Incuron, LLC, Buffalo, NY 14203, USA.
10
Buffalo BioLabs, LLC, Buffalo, NY 14203, USA.
11
Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
12
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.
13
Incuron, LLC, Buffalo, NY 14203, USA. Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
14
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.
15
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.
16
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.

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.

PMID:
26537256
PMCID:
PMC6207083
DOI:
10.1126/scitranslmed.aab1803
[Indexed for MEDLINE]
Free PMC Article

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