1. Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design
- Author
-
Rokita, Jo Lynne, Rathi, Komal S, Cardenas, Maria F, Upton, Kristen A, Jayaseelan, Joy, Cross, Katherine L, Pfeil, Jacob, Egolf, Laura E, Way, Gregory P, Farrel, Alvin, Kendsersky, Nathan M, Patel, Khushbu, Gaonkar, Krutika S, Modi, Apexa, Berko, Esther R, Lopez, Gonzalo, Vaksman, Zalman, Mayoh, Chelsea, Nance, Jonas, McCoy, Kristyn, Haber, Michelle, Evans, Kathryn, McCalmont, Hannah, Bendak, Katerina, Böhm, Julia W, Marshall, Glenn M, Tyrrell, Vanessa, Kalletla, Karthik, Braun, Frank K, Qi, Lin, Du, Yunchen, Zhang, Huiyuan, Lindsay, Holly B, Zhao, Sibo, Shu, Jack, Baxter, Patricia, Morton, Christopher, Kurmashev, Dias, Zheng, Siyuan, Chen, Yidong, Bowen, Jay, Bryan, Anthony C, Leraas, Kristen M, Coppens, Sara E, Doddapaneni, HarshaVardhan, Momin, Zeineen, Zhang, Wendong, Sacks, Gregory I, Hart, Lori S, Krytska, Kateryna, Mosse, Yael P, Gatto, Gregory J, Sanchez, Yolanda, Greene, Casey S, Diskin, Sharon J, Vaske, Olena Morozova, Haussler, David, Gastier-Foster, Julie M, Kolb, E Anders, Gorlick, Richard, Li, Xiao-Nan, Reynolds, C Patrick, Kurmasheva, Raushan T, Houghton, Peter J, Smith, Malcolm A, Lock, Richard B, Raman, Pichai, Wheeler, David A, and Maris, John M
- Subjects
Biological Sciences ,Pediatric ,Rare Diseases ,Genetics ,Human Genome ,Pediatric Cancer ,Pediatric Research Initiative ,Clinical Research ,Orphan Drug ,Biotechnology ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Animals ,Cell Line ,Tumor ,Central Nervous System Neoplasms ,Child ,Clinical Trials as Topic ,Disease Models ,Animal ,Genomics ,Humans ,Mice ,Mutation ,Neuroblastoma ,Neurofibromin 1 ,Osteosarcoma ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Recurrence ,Rhabdomyosarcoma ,Sarcoma ,Ewing ,Tumor Suppressor Protein p53 ,Exome Sequencing ,Wilms Tumor ,Xenograft Model Antitumor Assays ,classifier ,copy number profiling ,patient-derived xenograft ,pediatric cancer ,preclinical testing ,relapse ,transcriptome sequencing ,whole-exome sequencing ,Pediatric cancer ,whole exome sequencing ,Biochemistry and Cell Biology ,Medical Physiology ,Biological sciences - 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.
- Published
- 2019