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Orthotopic patient-derived xenografts of paediatric solid tumours.
- 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.
- Subjects :
- Animals
Bortezomib pharmacology
Bortezomib therapeutic use
Camptothecin analogs & derivatives
Camptothecin pharmacology
Camptothecin therapeutic use
Cell Cycle Proteins antagonists & inhibitors
Child
Clone Cells
Drug Therapy, Combination
Epigenesis, Genetic
Female
Heterografts drug effects
Heterografts metabolism
Heterografts pathology
Heterografts transplantation
High-Throughput Screening Assays methods
Humans
Hydroxamic Acids pharmacology
Hydroxamic Acids therapeutic use
Indoles pharmacology
Indoles therapeutic use
Irinotecan
Mice
Neoplasms genetics
Nuclear Proteins antagonists & inhibitors
Panobinostat
Protein-Tyrosine Kinases antagonists & inhibitors
Pyrazoles pharmacology
Pyrazoles therapeutic use
Pyrimidines pharmacology
Pyrimidines therapeutic use
Pyrimidinones
Rhabdomyosarcoma drug therapy
Rhabdomyosarcoma genetics
Vincristine pharmacology
Vincristine therapeutic use
Neoplasms drug therapy
Xenograft Model Antitumor Assays methods
Subjects
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