Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design
Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design
复制标题
DOI：
10.1016/j.celrep.2019.09.071
复制
发表时间：
2019-11-05
期刊：
影响因子：
8.8
通讯作者：
Maris, John M.
中科院分区：
文献类型：
--
作者：
Rokita, Jo Lynne;Rathi, Komal S.;Maris, John M.
加速癌症儿童的治疗仍然是一个迫在眉睫的挑战，这是由于组织结构之间和组织内部广泛的致癌基因异质性，在诊断和复发疾病之间演变的不同分子机制，以及有限的治疗选择。为了系统地对临床前小鼠模型中的新药物进行优先排序和合理测试，儿科临床前测试联盟的研究人员正在不断开发来自高危儿童癌症的患者来源的异种移植物(PDX)-其中许多对当前的护理标准治疗是无效的。在这里，我们描述了来自37个独特的儿科癌症的261个PDX模型的基因组特征；展示了组织学和亚型的真实概括；并完善了我们对复发疾病的理解。此外，我们使用表达信号来分类肿瘤的TP53和NF1途径失活。我们预计这些数据将作为儿科肿瘤学药物开发的资源，并将指导癌症儿童的合理临床试验设计。
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.