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Nature. 2017 Sep 7;549(7670):96-100. doi: 10.1038/nature23647. Epub 2017 Aug 30.

Orthotopic patient-derived xenografts of paediatric solid tumours.

Author information

1
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
2
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
3
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
4
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
5
Department of Small Animal Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
6
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
7
Department of the Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
8
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
9
The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63108, USA.
10
Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63108, USA.
11
Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63108, USA.
12
Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63108, USA.
13
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
14
Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.

Abstract

Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages. 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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PMID:
28854174
PMCID:
PMC5659286
DOI:
10.1038/nature23647
[Indexed for MEDLINE]
Free PMC Article

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