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Author Notes:

Michael A. Dyer, Department of Developmental Neurobiology, MS 323, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-3678, USA, Phone: (901) 595-2257; Fax: (901) 595-3143; michael.dyer@stjude.org

E.S. and M.A.D. designed the study and wrote the paper. S.F. wrote and supervised the protocol. X.C. and B.X. performed all computational analyses. C.B., B.G, V.H., M.O., K.B., J.D. assisted with preclinical animal studies and cell screening. J.E. assisted with molecular analyses. M.C. and A.B. provided pathology review. B.F. performed pharmacokinetic analysis. J.W. performed biostatistics. N.T. and A.S. analyzed drug sensitivity data. A.K. manages the CSTN and assisted with drug screening. X.Z. developed the protein paint visualization. E.R.M., R.K.W., J.D., J.Z., A.P. and M.A.D. contributed to the Pediatric Cancer Genome Project.

We thank Angela McArthur for editing the manuscript.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by Cancer Center Support (CA21765), grants to M.A.D from the NIH (EY014867, EY018599, and CA168875), and American Lebanese Syrian Associated Charities (ALSAC). M.A.D. was also supported by HHMI, Alex Lemonade Stand, Tully Family and Peterson Foundations. E.S. was supported by the St. Baldrick’s Foundation and the National Pediatric Cancer Foundation (NPCF).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • PANOBINOSTAT LBH589
  • GENOMIC LANDSCAPE
  • MULTIPLE-MYELOMA
  • CANCER
  • DISCOVERY
  • HETEROGENEITY
  • BORTEZOMIB
  • INHIBITOR
  • BIOBANK
  • MODELS

Orthotopic patient-derived xenografts of paediatric solid tumours

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Journal Title:

NATURE

Volume:

Volume 549, Number 7670

Publisher:

, Pages 96-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages1. 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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