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

Author

Rokita, JL, Rathi, KS, Cardenas, MF, Upton, KA, Jayaseelan, J, Cross, KL, Pfeil, J, Egolf, LE, Way, GP, Farrel, A, Kendsersky, NM, Patel, K, Gaonkar, KS, Modi, A, Berko, ER, Lopez, G, Vaksman, Z, Mayoh, C, Nance, J, McCoy, K, Haber, M, Evans, K, McCalmont, H, Bendak, K, Böhm, JW, Marshall, GM, Tyrrell, V, Kalletla, K, Braun, FK, Qi, L, Du, Y, Zhang, H, Lindsay, HB, Zhao, S, Shu, J, Baxter, P, Morton, C, Kurmashev, D, Zheng, S, Chen, Y, Bowen, J, Bryan, AC, Leraas, KM, Coppens, SE, Doddapaneni, HV, Momin, Z, Zhang, W, Sacks, GI, Hart, LS, Krytska, K, Mosse, YP, Gatto, GJ, Sanchez, Y, Greene, CS, Diskin, SJ, Vaske, OM, Haussler, D, Gastier-Foster, JM, Kolb, EA, Gorlick, R, Li, XN, Reynolds, CP, Kurmasheva, RT, Houghton, PJ, Smith, MA, Lock, RB, Raman, P, Wheeler, DA, Maris, JM, Rokita, JL, Rathi, KS, Cardenas, MF, Upton, KA, Jayaseelan, J, Cross, KL, Pfeil, J, Egolf, LE, Way, GP, Farrel, A, Kendsersky, NM, Patel, K, Gaonkar, KS, Modi, A, Berko, ER, Lopez, G, Vaksman, Z, Mayoh, C, Nance, J, McCoy, K, Haber, M, Evans, K, McCalmont, H, Bendak, K, Böhm, JW, Marshall, GM, Tyrrell, V, Kalletla, K, Braun, FK, Qi, L, Du, Y, Zhang, H, Lindsay, HB, Zhao, S, Shu, J, Baxter, P, Morton, C, Kurmashev, D, Zheng, S, Chen, Y, Bowen, J, Bryan, AC, Leraas, KM, Coppens, SE, Doddapaneni, HV, Momin, Z, Zhang, W, Sacks, GI, Hart, LS, Krytska, K, Mosse, YP, Gatto, GJ, Sanchez, Y, Greene, CS, Diskin, SJ, Vaske, OM, Haussler, D, Gastier-Foster, JM, Kolb, EA, Gorlick, R, Li, XN, Reynolds, CP, Kurmasheva, RT, Houghton, PJ, Smith, MA, Lock, RB, Raman, P, Wheeler, DA, and Maris, JM

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

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

Author

Rokita JL, Rathi KS, Cardenas MF, Upton KA, Jayaseelan J, Cross KL, Pfeil J, Egolf LE, Way GP, Farrel A, Kendsersky NM, Patel K, Gaonkar KS, Modi A, Berko ER, Lopez G, Vaksman Z, Mayoh C, Nance J, McCoy K, Haber M, Evans K, McCalmont H, Bendak K, Böhm JW, Marshall GM, Tyrrell V, Kalletla K, Braun FK, Qi L, Du Y, Zhang H, Lindsay HB, Zhao S, Shu J, Baxter P, Morton C, Kurmashev D, Zheng S, Chen Y, Bowen J, Bryan AC, Leraas KM, Coppens SE, Doddapaneni H, Momin Z, Zhang W, Sacks GI, Hart LS, Krytska K, Mosse YP, Gatto GJ, Sanchez Y, Greene CS, Diskin SJ, Vaske OM, Haussler D, Gastier-Foster JM, Kolb EA, Gorlick R, Li XN, Reynolds CP, Kurmasheva RT, Houghton PJ, Smith MA, Lock RB, Raman P, Wheeler DA, and Maris JM

Subjects
Animals, Cell Line, Tumor, Central Nervous System Neoplasms metabolism, Child, Clinical Trials as Topic, Disease Models, Animal, Genomics, Humans, Mice, Mutation, Neuroblastoma genetics, Neuroblastoma metabolism, Neurofibromin 1 genetics, Neurofibromin 1 metabolism, Osteosarcoma genetics, Osteosarcoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Recurrence, Rhabdomyosarcoma genetics, Rhabdomyosarcoma metabolism, Sarcoma, Ewing genetics, Sarcoma, Ewing metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Exome Sequencing, Wilms Tumor genetics, Wilms Tumor metabolism, Central Nervous System Neoplasms genetics, Neurofibromin 1 antagonists & inhibitors, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Tumor Suppressor Protein p53 antagonists & inhibitors, Xenograft Model Antitumor Assays
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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2019
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