Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trial design
Author:
Rokita Jo LynneORCID, Rathi Komal S., Cardenas Maria F., Upton Kristen A., Jayaseelan Joy, Cross Katherine L., Pfeil Jacob, Ritenour Laura E., Modi Apexa, Farrel Alvin, Way Gregory P.ORCID, Kendsersky Nathan M.ORCID, Patel Khushbu, Lopez GonzaloORCID, Vaksman ZalmanORCID, Mayoh ChelseaORCID, Nance Jonas, McCoy Kristyn, Haber MichelleORCID, Evans Kathryn, McCalmont Hannah, Bendak Katerina, Böhm Julia W., Marshall Glenn M., Tyrrell Vanessa, Kalletla KarthikORCID, 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.ORCID, Diskin Sharon J., Vaske Olena Morozova, Haussler DavidORCID, 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., Maris John M.
Abstract
SummaryAccelerating cures for children with cancer remains an immediate challenge due to 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) from high-risk childhood cancers, many refractory to current standard-of-care treatments. Here, we genomically characterize 261 PDX models from 29 unique pediatric cancer malignancies and demonstrate faithful recapitulation of histologies, subtypes, and refine our understanding of relapsed disease. Expression and mutational signatures are used to classify tumors forTP53andNF1inactivation, as well as impaired DNA repair. We anticipate that these data will serve as a resource for pediatric oncology drug development and guide rational clinical trial design for children with cancer.HighlightsMultiplatform genomic analysis defines landscape of 261 pediatric cancer patient derived xenograft (PDX) modelsPediatric patient derived xenografts faithfully recapitulate relapsed diseaseInferredTP53pathway inactivation correlates with pediatric cancer copy number burdenSomatic mutational signatures predict impaired DNA repair across multiple histologies
Publisher
Cold Spring Harbor Laboratory
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