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

Research output: Contribution to journalArticlepeer-review

166 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 languageEnglish
Pages (from-to)96-100
Number of pages5
JournalNature
Volume549
Issue number7670
DOIs
StatePublished - Sep 7 2017

Bibliographical note

Funding Information:
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.

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

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Orthotopic patient-derived xenografts of paediatric solid tumours'. Together they form a unique fingerprint.

Cite this