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Orthotopic patient-derived xenografts of paediatric solid tumours
Open accessAbstract
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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“These PDX model systems are of particular value in both basic science and potentially personalized medicine research 180,183,222 as they have clinical and molecular features that are quite representative of the human disease 223,224,225,226 .”
From Osteosarcoma (2022) · cites this paper as [223]
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Metadata
- 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
- Venue
- Nature
- Published
- 2017-08-30
- Volume
- 549
- Issue
- 7670
- Pages
- 96-100
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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