文章：

儿童实体瘤的分子特征和治疗脆弱性

Molecular characteristics and therapeutic vulnerabilities across paediatric solid tumours

原文发布日期：2019-07-12

DOI: 10.1038/s41568-019-0169-x

类型: Review Article

开放获取: 否

英文摘要：

The spectrum of tumours arising in childhood is fundamentally different from that seen in adults, and they are known to be divergent from adult malignancies in terms of cellular origins, epidemiology, genetic complexity, driver mutations and underlying mutational processes. Despite the immense knowledge generated through sequencing efforts and functional characterization of identified (epi-)genetic alterations over the past decade, the clinical implications of this knowledge have so far been limited. Novel preclinical platforms such as the European Innovative Therapies for Children with Cancer–Paediatric Preclinical Proof-of-Concept Platform and the US-based Pediatric Preclinical Testing Consortium are being developed to try to change this by aiming to recapitulate the extensive heterogeneity of paediatric tumours and thereby, hopefully, improve the ability to predict clinical benefit. Numerous studies have also been established worldwide to provide patients with access to real-time molecular profiling and the possibility of more precise mechanism-of-action-based treatments. In addition to tumour-intrinsic findings and mechanisms, ongoing studies are investigating features such as the immune microenvironment of paediatric tumours in comparison with adult cancers — currently of very timely clinical relevance. However, there is an ongoing need for rigorous preclinical biomarker and target validation to feed into the next generation of molecularly stratified clinical trials. This Review aims to provide a comprehensive state-of-the-art overview of the molecular landscape of paediatric solid tumours, including their underlying genomic alterations and interactions with the microenvironment, complemented with our current understanding of potential therapeutic vulnerabilities and how these can be preclinically tested using more accurate predictive methods. Finally, we provide an outlook on the challenges and opportunities associated with translating this overwhelming scientific progress into real clinical benefit.

摘要翻译： 

儿童期发生的肿瘤谱与成人肿瘤有着根本差异，且在细胞起源、流行病学、遗传复杂性、驱动突变及潜在突变过程方面均与成人恶性肿瘤存在显著区别。尽管过去十年通过测序研究和表观遗传学改变的功能表征已积累大量知识，但这些知识的临床转化应用仍十分有限。欧洲儿童癌症创新疗法-临床前概念验证平台和美国儿科临床前测试联盟等新型临床前平台正致力于改变这一现状，通过重现儿童肿瘤的广泛异质性，以期提升临床疗效预测能力。全球范围内已建立众多研究项目，为患者提供实时分子谱分析服务，并推动更精准的靶向机制治疗的应用。除肿瘤内在特征与机制外，当前研究还持续探索儿童肿瘤免疫微环境等特征与成人癌症的差异——这一领域具有迫切的临床相关性。然而， rigorous 的临床前生物标志物与靶点验证仍是推动下一代分子分层临床试验的关键。本综述旨在系统阐述儿童实体瘤的分子景观研究现状，包括其基因组改变与微环境相互作用，并结合当前对治疗脆弱性的认知及如何通过更精准的预测方法进行临床前验证。最后，我们将展望如何将这一迅猛发展的科学成果转化为实际临床效益所面临的挑战与机遇。

原文链接：

Molecular characteristics and therapeutic vulnerabilities across paediatric solid tumours