Cited by 290Cancer Genomics and DiagnosticsCancer Cells and MetastasisAcute Lymphoblastic Leukemia research

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Orthotopic patient-derived xenografts of paediatric solid tumours

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Stewart, Elizabeth, Federico, Sara M., Chen, Xiang, Shelat, Anang A., Bradley, Cori, Gordon, Brittney, Karlstrom, Asa, Twarog, Nathaniel R., Clay, Michael R., Bahrami, Armita, Freeman, Burgess B., Xu, Beisi, Zhou, Xin, Wu, Jianrong, Honnell, Victoria, Ocarz, Monica, Blankenship, Kaley, Dapper, Jason, Mardis, Elaine R., Wilson, Richard K., Downing, James, Zhang, Jinghui, Easton, John, Pappo, Alberto, Dyer, Michael A.·2017·Nature

DOI 10.1038/nature23647PMC PMC5659286

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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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Self-citation

Authors: 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., Wilson, R. K., Downing, J., Zhang, J., Easton, J., Pappo, A., & Dyer, M. A.
Affiliations: St. Jude Children's Research Hospital (US)
Washington University in St. Louis (US)
Corresponding author: Dyer, Michael A.
ORCID: Stewart, Elizabeth
Federico, Sara M.
Chen, Xiang
Shelat, Anang A.
Twarog, Nathaniel R.
Clay, Michael R.
Bahrami, Armita
Freeman, Burgess B.
Xu, Beisi
Zhou, Xin
Wu, Jianrong
Honnell, Victoria
Mardis, Elaine R.
Wilson, Richard K.
Downing, James
Zhang, Jinghui
Easton, John
Pappo, Alberto
Dyer, Michael A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-08-30
Volume: 549
Issue: 7670
Pages: 96-100
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature23647
PMC: PMC5659286
OpenAlex: W2750663875
Cited by: 286
References: 30
Citations by year: 2026: 19 · 2025: 20 · 2024: 31 · 2023: 32 · 2022: 33 · 2021: 47 · 2020: 46 · 2019: 31 · 2018: 24 · 2017: 3
FWCI: 9.31
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Howard Hughes Medical Institute
National Eye Institute (R01EY014867, R01EY018599)
National Cancer Institute (R01CA219686, R01CA168875, P30CA021765)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
Keywords: pediatric solid tumors, rhabdomyosarcoma, tumor recurrence, clonal analysis, drug screening, predictive biomarkers, WEE1 inhibitor, AZD1775, irinotecan, vincristine, combination therapy, cancer cell lines
MeSH terms: Bortezomib, Irinotecan, Panobinostat, Animals, Camptothecin, Child, Clone Cells, Drug Therapy, Combination, Female, Humans, Hydroxamic Acids, Indoles, Neoplasms, Nuclear Proteins, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Pyrimidinones, Rhabdomyosarcoma, Vincristine, Cell Cycle Proteins, Xenograft Model Antitumor Assays, Epigenesis, Genetic, Mice, High-Throughput Screening Assays, Heterografts

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