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

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

Roswell Park - Cell Stress and Biophysical Oncology

University of New South Wales
Prince of Wales Hospital
Yale University
University of Cologne
Max Planck Institute for Metabolism Research
The Children's Hospital at Westmead
The University of Sydney
LLC
Ghent University
Sydney Children's Hospital
Roswell Park Cancer Institute

Research output: Contribution to journal › Article › peer-review

121 Scopus citations

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.

Original language	English
Article number	312ra176
Journal	Science Translational Medicine
Volume	7
Issue number	312
DOIs	https://doi.org/10.1126/scitranslmed.aab1803
State	Published - Nov 4 2015

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Carter, D. R., Murray, J., Cheung, B. B., Gamble, L., Koach, J., Tsang, J., Sutton, S., Kalla, H., Syed, S., Gifford, A. J., Issaeva, N., Biktasova, A., Atmadibrata, B., Sun, Y., Sokolowski, N., Ling, D., Kim, P. Y., Webber, H., Clark, A., ... Marshall, G. M. (2015). Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma. Science Translational Medicine, 7(312), Article 312ra176. https://doi.org/10.1126/scitranslmed.aab1803

@article{32422db8f20e4efcb616c26c5311d408,

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.",

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

year = "2015",

month = nov,

day = "4",

doi = "10.1126/scitranslmed.aab1803",

language = "English",

volume = "7",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

number = "312",

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Carter, DR, Murray, J, Cheung, BB, Gamble, L, Koach, J, Tsang, J, Sutton, S, Kalla, H, Syed, S, Gifford, AJ, Issaeva, N, Biktasova, A, Atmadibrata, B, Sun, Y, Sokolowski, N, Ling, D, Kim, PY, Webber, H, Clark, A, Ruhle, M, Liu, B, Oberthuer, A, Fischer, M, Byrne, J, Saletta, F, Thwe, LM, Purmal, A, Haderski, G, Burkhart, C, Speleman, F, De Preter, K, Beckers, A, Ziegler, DS, Liu, T, Gurova, KV, Gudkov, AV, Norris, MD, Haber, M & Marshall, GM 2015, 'Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma', Science Translational Medicine, vol. 7, no. 312, 312ra176. https://doi.org/10.1126/scitranslmed.aab1803

TY - JOUR

T1 - Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma

AU - Carter, Daniel R.

AU - Murray, Jayne

AU - Cheung, Belamy B.

AU - Gamble, Laura

AU - Koach, Jessica

AU - Tsang, Joanna

AU - Sutton, Selina

AU - Kalla, Heyam

AU - Syed, Sarah

AU - Gifford, Andrew J.

AU - Issaeva, Natalia

AU - Biktasova, Asel

AU - Atmadibrata, Bernard

AU - Sun, Yuting

AU - Sokolowski, Nicolas

AU - Ling, Dora

AU - Kim, Patrick Y.

AU - Webber, Hannah

AU - Clark, Ashleigh

AU - Ruhle, Michelle

AU - Liu, Bing

AU - Oberthuer, André

AU - Fischer, Matthias

AU - Byrne, Jennifer

AU - Saletta, Federica

AU - Thwe, Le Myo

AU - Purmal, Andrei

AU - Haderski, Gary

AU - Burkhart, Catherine

AU - Speleman, Frank

AU - De Preter, Katleen

AU - Beckers, Anneleen

AU - Ziegler, David S.

AU - Liu, Tao

AU - Gurova, Katerina V.

AU - Gudkov, Andrei V.

AU - Norris, Murray D.

AU - Haber, Michelle

AU - Marshall, Glenn M.

PY - 2015/11/4

Y1 - 2015/11/4

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84946807490

U2 - 10.1126/scitranslmed.aab1803

DO - 10.1126/scitranslmed.aab1803

M3 - Article

C2 - 26537256

AN - SCOPUS:84946807490

SN - 1946-6234

VL - 7

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 312

M1 - 312ra176

ER -

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

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