Orthotopic patient-derived xenografts of paediatric solid tumours

Elizabeth Stewart; Sara M. Federico; Xiang Chen; Anang A. Shelat; Cori Bradley; Brittney Gordon; Asa Karlstrom; Nathaniel R. Twarog; Michael R. Clay; Armita Bahrami; Burgess B. Freeman; Beisi Xu; Xin Zhou; Jianrong Wu; Victoria Honnell; Monica Ocarz; Kaley Blankenship; Jason Dapper; Elaine R. Mardis; Richard K. Wilson; James Downing; Jinghui Zhang; John Easton; Alberto Pappo; Michael A. Dyer

doi:10.1038/nature23647

Orthotopic patient-derived xenografts of paediatric solid tumours

Elizabeth Stewart, Sara M. Federico, Xiang Chen, Anang A. Shelat, Cori Bradley, Brittney Gordon, Asa Karlstrom, Nathaniel R. Twarog, Michael R. Clay, Armita Bahrami, Burgess B. Freeman, Beisi Xu, Xin Zhou, Jianrong Wu, Victoria Honnell, Monica Ocarz, Kaley Blankenship, Jason Dapper, Elaine R. Mardis, Richard K. WilsonJames Downing, Jinghui Zhang, John Easton, Alberto Pappo, Michael A. Dyer

Internal Medicine

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

213 Scopus citations

Abstract

Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages¹. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo.

Original language	English
Pages (from-to)	96-100
Number of pages	5
Journal	Nature
Volume	549
Issue number	7670
DOIs	https://doi.org/10.1038/nature23647
State	Published - Sep 7 2017

Bibliographical note

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Funding

Acknowledgements We thank A. McArthur for editing the manuscript. This work was supported by Cancer Center Support (CA21765), grants to M.A.D. from the National Institutes of Health (EY014867, EY018599, and CA168875), and American Lebanese Syrian Associated Charities. M.A.D. was also supported by the Howard Hughes Medical Institute, Alex Lemonade Stand, Tully Family and Peterson Foundations. E.S. was supported by the St. Baldrick’s Foundation and the National Pediatric Cancer Foundation.

Funders	Funder number
Markey Cancer Center's Cancer Center Support	CA21765
National Pediatric Cancer Foundation
St. Baldrick’s Foundation
National Institutes of Health (NIH)	EY018599, CA168875, EY014867
Howard Hughes Medical Institute
National Childhood Cancer Registry – National Cancer Institute	R01CA219686
Alex's Lemonade Stand Foundation for Childhood Cancer
American Lebanese Syrian Associated Charities

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Stewart, E., Federico, S. M., Chen, X., Shelat, A. A., Bradley, C., Gordon, B., Karlstrom, A., Twarog, N. R., Clay, M. R., Bahrami, A., Freeman, B. B., Xu, B., Zhou, X., Wu, J., Honnell, V., Ocarz, M., Blankenship, K., Dapper, J., Mardis, E. R., ... Dyer, M. A. (2017). Orthotopic patient-derived xenografts of paediatric solid tumours. Nature, 549(7670), 96-100. https://doi.org/10.1038/nature23647

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title = "Orthotopic patient-derived xenografts of paediatric solid tumours",

abstract = "Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages1. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo.",

author = "Elizabeth Stewart and Federico, {Sara M.} and Xiang Chen and Shelat, {Anang A.} and Cori Bradley and Brittney Gordon and Asa Karlstrom and Twarog, {Nathaniel R.} and Clay, {Michael R.} and Armita Bahrami and Freeman, {Burgess B.} and Beisi Xu and Xin Zhou and Jianrong Wu and Victoria Honnell and Monica Ocarz and Kaley Blankenship and Jason Dapper and Mardis, {Elaine R.} and Wilson, {Richard K.} and James Downing and Jinghui Zhang and John Easton and Alberto Pappo and Dyer, {Michael A.}",

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Stewart, E, Federico, SM, Chen, X, Shelat, AA, Bradley, C, Gordon, B, Karlstrom, A, Twarog, NR, Clay, MR, Bahrami, A, Freeman, BB, Xu, B, Zhou, X, Wu, J, Honnell, V, Ocarz, M, Blankenship, K, Dapper, J, Mardis, ER, Wilson, RK, Downing, J, Zhang, J, Easton, J, Pappo, A & Dyer, MA 2017, 'Orthotopic patient-derived xenografts of paediatric solid tumours', Nature, vol. 549, no. 7670, pp. 96-100. https://doi.org/10.1038/nature23647

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AU - Stewart, Elizabeth

AU - Federico, Sara M.

AU - Chen, Xiang

AU - Shelat, Anang A.

AU - Bradley, Cori

AU - Gordon, Brittney

AU - Karlstrom, Asa

AU - Twarog, Nathaniel R.

AU - Clay, Michael R.

AU - Bahrami, Armita

AU - Freeman, Burgess B.

AU - Xu, Beisi

AU - Zhou, Xin

AU - Wu, Jianrong

AU - Honnell, Victoria

AU - Ocarz, Monica

AU - Blankenship, Kaley

AU - Dapper, Jason

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Downing, James

AU - Zhang, Jinghui

AU - Easton, John

AU - Pappo, Alberto

AU - Dyer, Michael A.

PY - 2017/9/7

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N2 - Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages1. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo.

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Orthotopic patient-derived xenografts of paediatric solid tumours

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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