Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design

Jo Lynne Rokita, Komal S. Rathi, Maria F. Cardenas, Kristen A. Upton, Joy Jayaseelan, Katherine L. Cross, Jacob Pfeil, Laura E. Egolf, Gregory P. Way, Alvin Farrel, Nathan M. Kendsersky, Khushbu Patel, Krutika S. Gaonkar, Apexa Modi, Esther R. Berko, Gonzalo Lopez, Zalman Vaksman, Chelsea Mayoh, Jonas Nance, Kristyn McCoyMichelle Haber, Kathryn Evans, Hannah McCalmont, Katerina Bendak, Julia W. Böhm, Glenn M. Marshall, Vanessa Tyrrell, Karthik Kalletla, Frank K. Braun, Lin Qi, Yunchen Du, Huiyuan Zhang, Holly B. Lindsay, Sibo Zhao, Jack Shu, Patricia Baxter, Christopher Morton, Dias Kurmashev, Siyuan Zheng, Yidong Chen, Jay Bowen, Anthony C. Bryan, Kristen M. Leraas, Sara E. Coppens, Harsha Vardhan Doddapaneni, Zeineen Momin, Wendong Zhang, Gregory I. Sacks, Lori S. Hart, Kateryna Krytska, Yael P. Mosse, Gregory J. Gatto, Yolanda Sanchez, Casey S. Greene, Sharon J. Diskin, Olena Morozova Vaske, David Haussler, Julie M. Gastier-Foster, E. Anders Kolb, Richard Gorlick, Xiao Nan Li, C. Patrick Reynolds, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock, Pichai Raman, David A. Wheeler, John M. Maris*

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)—many of which are refractory to current standard-of-care treatments—from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.

Original languageEnglish (US)
Pages (from-to)1675-1689.e9
JournalCell reports
Volume29
Issue number6
DOIs
StatePublished - Nov 5 2019

Keywords

  • classifier
  • copy number profiling
  • patient-derived xenograft
  • pediatric cancer
  • preclinical testing
  • relapse
  • transcriptome sequencing
  • whole-exome sequencing

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Rokita, J. L., Rathi, K. S., Cardenas, M. F., Upton, K. A., Jayaseelan, J., Cross, K. L., Pfeil, J., Egolf, L. E., Way, G. P., Farrel, A., Kendsersky, N. M., Patel, K., Gaonkar, K. S., Modi, A., Berko, E. R., Lopez, G., Vaksman, Z., Mayoh, C., Nance, J., ... Maris, J. M. (2019). Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design. Cell reports, 29(6), 1675-1689.e9. https://doi.org/10.1016/j.celrep.2019.09.071