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Orthotopic patient-derived xenografts of paediatric solid tumours.

Authors :
Stewart E
Federico SM
Chen X
Shelat AA
Bradley C
Gordon B
Karlstrom A
Twarog NR
Clay MR
Bahrami A
Freeman BB 3rd
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
Source :
Nature [Nature] 2017 Sep 07; Vol. 549 (7670), pp. 96-100. Date of Electronic Publication: 2017 Aug 30.
Publication Year :
2017

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.

Details

Language :
English
ISSN :
1476-4687
Volume :
549
Issue :
7670
Database :
MEDLINE
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
28854174
Full Text :
https://doi.org/10.1038/nature23647