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

Autor:	Malcolm A. Smith, Xiao-Nan Li, Kateryna Krytska, Anthony C. Bryan, Gregory I. Sacks, Raushan T. Kurmasheva, Huiyuan Zhang, Joy Jayaseelan, Dias Kurmashev, Richard Gorlick, Gregory Gatto, Jo Lynne Rokita, Kathryn Evans, Maria F. Cardenas, Frank K. Braun, Alvin Farrel, Julie M. Gastier-Foster, Yael P. Mosse, Jonas Nance, Yolanda Sanchez, Gonzalo Lopez, Apexa Modi, Sara E. Coppens, Nathan M. Kendsersky, Esther R. Berko, Gregory P. Way, Wendong Zhang, Pichai Raman, David Haussler, Yi Chen, Julia W. Böhm, Zeineen Momin, Yunchen Du, E. Anders Kolb, Jay Bowen, David A. Wheeler, Lori S. Hart, Sibo Zhao, Harshavardhan Doddapaneni, Khushbu Patel, Vanessa Tyrrell, Christopher L. Morton, Hannah McCalmont, Zalman Vaksman, Siyuan Zheng, Casey S. Greene, Laura E. Egolf, Chelsea Mayoh, C. Patrick Reynolds, Kristyn McCoy, Jack Shu, Lin Qi, Olena M. Vaske, Holly Lindsay, John M. Maris, Richard B. Lock, Krutika S. Gaonkar, Jacob Pfeil, Sharon J. Diskin, Michelle Haber, Patricia Baxter, Kristen M. Leraas, Katerina Bendak, Komal S. Rathi, Peter J. Houghton, Glenn M. Marshall, Katherine L. Cross, Kristen A. Upton, Karthik Kalletla
Rok vydání:	2019
Předmět:	0301 basic medicine Oncology Genomic profiling Pediatric cancer Medical Physiology Whole Exome Sequencing Central Nervous System Neoplasms Mice Neuroblastoma 0302 clinical medicine Recurrence Rhabdomyosarcoma 2.1 Biological and endogenous factors whole-exome sequencing Aetiology Child lcsh:QH301-705.5 classifier Exome sequencing Tumor xenograft Cancer Pediatric relapse Osteosarcoma Clinical Trials as Topic Tumor Neurofibromin 1 Sarcoma Genomics Precursor Cell Lymphoblastic Leukemia-Lymphoma 3. Good health Drug development 5.1 Pharmaceuticals Preclinical testing Development of treatments and therapeutic interventions preclinical testing Childhood Tumor Biotechnology Pediatric Research Initiative medicine.medical_specialty patient-derived xenograft Sarcoma Ewing transcriptome sequencing Wilms Tumor Article General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Rare Diseases Clinical Research Cell Line Tumor Ewing Internal medicine Exome Sequencing Genetics medicine Animals Humans copy number profiling Animal business.industry Clinical study design Human Genome medicine.disease Xenograft Model Antitumor Assays Disease Models Animal Orphan Drug Good Health and Well Being 030104 developmental biology lcsh:Biology (General) Disease Models Mutation Biochemistry and Cell Biology Tumor Suppressor Protein p53 business 030217 neurology & neurosurgery
Zdroj:	Cell reports, vol 29, iss 6 Cell Reports, Vol 29, Iss 6, Pp 1675-1689.e9 (2019) Cell reports
ISSN:	1556-5068
DOI:	10.2139/ssrn.3377367
Popis:	SUMMARY 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. Graphical Abstract In Brief Rokita et. al provide an extensively annotated genomic dataset of somatic oncogenic regulation across 37 distinct pediatric malignancies. The 261 patient-derived xenograft models are available to the scientific community, and the genomic annotations will enable rational preclinical agent prioritization and acceleration of therapeutic targets for early-phase pediatric oncology clinical trials.
Databáze:	OpenAIRE
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