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

Daniel R Carter; Jayne Murray; Belamy B Cheung; Laura Gamble; Jessica Koach; Joanna Tsang; Selina Sutton; Heyam Kalla; Sarah Syed; Andrew J Gifford; Natalia Issaeva; Asel Biktasova; Bernard Atmadibrata; Yuting Sun; Nicolas Sokolowski; Dora Ling; Patrick Y Kim; Hannah Webber; Ashleigh Clark; Michelle Ruhle; Bing Liu; André Oberthuer; Matthias Fischer; Jennifer Byrne; Federica Saletta; Le Myo Thwe; Andrei Purmal; Gary Haderski; Catherine Burkhart; Frank Speleman; Katleen De Preter; Anneleen Beckers; David S Ziegler; Tao Liu; Katerina V Gurova; Andrei V Gudkov; Murray D Norris; Michelle Haber; Glenn M Marshall

doi:10.1126/scitranslmed.aab1803

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

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

Authors

Daniel R Carter¹, Jayne Murray², Belamy B Cheung¹, Laura Gamble², Jessica Koach², Joanna Tsang², Selina Sutton², Heyam Kalla², Sarah Syed², Andrew J Gifford³, Natalia Issaeva⁴, Asel Biktasova⁴, Bernard Atmadibrata², Yuting Sun², Nicolas Sokolowski², Dora Ling², Patrick Y Kim², Hannah Webber², Ashleigh Clark², Michelle Ruhle², Bing Liu², André Oberthuer⁵, Matthias Fischer⁶, Jennifer Byrne⁷, Federica Saletta⁸, Le Myo Thwe⁷, Andrei Purmal⁹, Gary Haderski¹⁰, Catherine Burkhart¹⁰, Frank Speleman¹¹, Katleen De Preter¹¹, Anneleen Beckers¹¹, David S Ziegler¹², Tao Liu¹¹, Katerina V Gurova¹³, Andrei V Gudkov¹³, Murray D Norris¹⁴, Michelle Haber¹⁵, Glenn M Marshall¹⁶

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Carbazoles / pharmacology*
Carbazoles / therapeutic use
DNA Repair / drug effects
DNA-Binding Proteins / antagonists & inhibitors*
DNA-Binding Proteins / metabolism
High Mobility Group Proteins / antagonists & inhibitors*
High Mobility Group Proteins / metabolism
Humans
Molecular Targeted Therapy
Nervous System Neoplasms / drug therapy*
Nervous System Neoplasms / metabolism*
Neuroblastoma / drug therapy*
Neuroblastoma / metabolism*
Proto-Oncogene Proteins c-myc / metabolism*
Signal Transduction / drug effects
Transcriptional Elongation Factors / antagonists & inhibitors*
Transcriptional Elongation Factors / metabolism

Substances

Antineoplastic Agents
CBLC137
Carbazoles
DNA-Binding Proteins
High Mobility Group Proteins
MYC protein, human
Proto-Oncogene Proteins c-myc
SSRP1 protein, human
Transcriptional Elongation Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding