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

TitleGenomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.
Publication TypeJournal Article
Year of Publication2019
AuthorsRokita, JLynne, 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, OMorozova, Haussler, D, Gastier-Foster, JM, E Kolb, A, Gorlick, R, Li, X-N, C Reynolds, P, Kurmasheva, RT, Houghton, PJ, Smith, MA, Lock, RB, Raman, P, Wheeler, DA, Maris, JM
JournalCell Rep
Volume29
Issue6
Pagination1675-1689.e9
Date Published2019 11 05
ISSN2211-1247
KeywordsAnimals, 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, Whole Exome Sequencing, Wilms Tumor, 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.

DOI10.1016/j.celrep.2019.09.071
Alternate JournalCell Rep
PubMed ID31693904
PubMed Central IDPMC6880934
Grant ListU01 CA199288 / CA / NCI NIH HHS / United States
UC2 HL103010 / HL / NHLBI NIH HHS / United States
U01 CA199000 / CA / NCI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
U01 CA199287 / CA / NCI NIH HHS / United States
L40 CA220942 / CA / NCI NIH HHS / United States
R35 CA220500 / CA / NCI NIH HHS / United States
U01 CA199222 / CA / NCI NIH HHS / United States
U01 CA199221 / CA / NCI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
R01 CA221957 / CA / NCI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
UC2 HL102926 / HL / NHLBI NIH HHS / United States
UC2 HL102923 / HL / NHLBI NIH HHS / United States
UC2 HL102924 / HL / NHLBI NIH HHS / United States
T32 CA009615 / CA / NCI NIH HHS / United States
U01 CA199297 / CA / NCI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
R01 NS095411 / NS / NINDS NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
UC2 HL102925 / HL / NHLBI NIH HHS / United States