Dataset Information

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

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.

SUBMITTER: Rokita JL

PROVIDER: S-EPMC6880934 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Rokita Jo Lynne JL Rathi Komal S KS Cardenas Maria F MF Upton Kristen A KA Jayaseelan Joy J Cross Katherine L KL Pfeil Jacob J Egolf Laura E LE Way Gregory P GP Farrel Alvin A Kendsersky Nathan M NM Patel Khushbu K Gaonkar Krutika S KS Modi Apexa A Berko Esther R ER Lopez Gonzalo G Vaksman Zalman Z Mayoh Chelsea C Nance Jonas J McCoy Kristyn K Haber Michelle M Evans Kathryn K McCalmont Hannah H Bendak Katerina K Böhm Julia W JW Marshall Glenn M GM Tyrrell Vanessa V Kalletla Karthik K Braun Frank K FK Qi Lin L Du Yunchen Y Zhang Huiyuan H Lindsay Holly B HB Zhao Sibo S Shu Jack J Baxter Patricia P Morton Christopher C Kurmashev Dias D Zheng Siyuan S Chen Yidong Y Bowen Jay J Bryan Anthony C AC Leraas Kristen M KM Coppens Sara E SE Doddapaneni HarshaVardhan H Momin Zeineen Z Zhang Wendong W Sacks Gregory I GI Hart Lori S LS Krytska Kateryna K Mosse Yael P YP Gatto Gregory J GJ Sanchez Yolanda Y Greene Casey S CS Diskin Sharon J SJ Vaske Olena Morozova OM Haussler David D Gastier-Foster Julie M JM Kolb E Anders EA Gorlick Richard R Li Xiao-Nan XN Reynolds C Patrick CP Kurmasheva Raushan T RT Houghton Peter J PJ Smith Malcolm A MA Lock Richard B RB Raman Pichai P Wheeler David A DA Maris John M JM

Cell reports 20191101 6

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 ...[more]

PMID: 31693904

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Project description:BackgroundEndometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models.MethodsHere, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC.ResultsPDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature.ConclusionsEC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.

Dataset Information

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

Publications

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

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