Journal Article

Orthotopic patient-derived xenografts of paediatric solid tumours

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

2017

Overview

A protocol producing orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy demonstrates proof of principle for using these tumours for basic and translational research on paediatric solid tumours. Xenograft archive Preclinical models of paediatric solid tumours that could help identify predictive biomarkers of a patient's sensitivity to therapy have been lacking. Over five years, the authors have developed an open access collection of orthotopic xenografts of 12 types of paediatric tumour. Genomic and epigenetic characterization reveals that xenografts retain characteristics of the tumour of origin. A high-throughput drug screen provides a resource for the community to identify potentially efficacious drug combinations. Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages 1 . Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30% 2 . 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 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 631/208/68/2486 / 631/67/70 / Animals / Autopsy / Bortezomib - pharmacology / Bortezomib - therapeutic use / Camptothecin - analogs & derivatives / Camptothecin - pharmacology / Camptothecin - therapeutic use / Cancer / Care and treatment / Cell Cycle Proteins - antagonists & inhibitors / Chemotherapy / Child / Children / Children & youth / Clone Cells / Diagnosis / Drug Therapy, Combination / Epigenesis, Genetic / Female / Gene expression / Genomes / Heterografts - drug effects / Heterografts - metabolism / Heterografts - pathology / Heterografts - transplantation / High-Throughput Screening Assays - methods / Humanities and Social Sciences / Humans / Hydroxamic Acids - pharmacology / Hydroxamic Acids - therapeutic use / Indoles - pharmacology / Indoles - therapeutic use / Irinotecan / letter / Methods / Mice / multidisciplinary / Multiple myeloma / Mutation / Neoplasms - drug therapy / Neoplasms - genetics / Neuroblastoma / Nuclear Proteins - antagonists & inhibitors / Panobinostat / Patients / Pediatric tumors / Pediatrics / Protein-Tyrosine Kinases - antagonists & inhibitors / Pyrazoles - pharmacology / Pyrazoles - therapeutic use / Pyrimidines - pharmacology / Pyrimidines - therapeutic use / Pyrimidinones / Rhabdomyosarcoma / Rhabdomyosarcoma - drug therapy / Rhabdomyosarcoma - genetics / Science / Tumors / Vincristine / Vincristine - pharmacology / Vincristine - therapeutic use / Xenograft Model Antitumor Assays - methods / Xenografts / Xenotransplantation