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Molecular characteristics and therapeutic vulnerabilities across paediatric solid tumours.
Nature Reviews Cancer ( IF 72.5 ) Pub Date : 2019-07-12 , DOI: 10.1038/s41568-019-0169-x David T W Jones 1, 2 , Ana Banito 1, 3 , Thomas G P Grünewald 4, 5 , Michelle Haber 6, 7 , Natalie Jäger 1, 8 , Marcel Kool 1, 8 , Till Milde 1, 9, 10 , Jan J Molenaar 11 , Arash Nabbi 12 , Trevor J Pugh 12, 13, 14 , Gudrun Schleiermacher 15, 16 , Malcolm A Smith 17 , Frank Westermann 1, 18 , Stefan M Pfister 1, 8, 10
Nature Reviews Cancer ( IF 72.5 ) Pub Date : 2019-07-12 , DOI: 10.1038/s41568-019-0169-x David T W Jones 1, 2 , Ana Banito 1, 3 , Thomas G P Grünewald 4, 5 , Michelle Haber 6, 7 , Natalie Jäger 1, 8 , Marcel Kool 1, 8 , Till Milde 1, 9, 10 , Jan J Molenaar 11 , Arash Nabbi 12 , Trevor J Pugh 12, 13, 14 , Gudrun Schleiermacher 15, 16 , Malcolm A Smith 17 , Frank Westermann 1, 18 , Stefan M Pfister 1, 8, 10
Affiliation
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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.
中文翻译：
跨儿科实体瘤的分子特征和治疗脆弱性。
儿童时期出现的肿瘤谱与成年人所见完全不同，众所周知，它们在细胞起源，流行病学，遗传复杂性，驱动基因突变和潜在的突变过程方面与成年人的恶性肿瘤有所不同。尽管在过去十年中通过测序工作和已鉴定的（表观）遗传变异的功能表征产生了巨大的知识，但迄今为止，该知识的临床意义仍然受到限制。正在开发新型临床前平台，例如欧洲针对儿童的癌症儿科临床前概念验证创新治疗平台和美国的儿科临床前测试联盟，以试图通过概括儿童肿瘤的广泛异质性来改变这一现状。因此，希望 提高预测临床获益的能力。全球范围内也已经建立了许多研究，以使患者能够获得实时分子谱分析，并有可能基于作用机理进行更精确的治疗。除了肿瘤内在的发现和机制外，正在进行的研究还在研究诸如与成人癌症相比的儿科肿瘤的免疫微环境等特征-目前具有非常及时的临床意义。然而，持续需要严格的临床前生物标志物和靶标验证，以用于下一代分子分层的临床试验。这篇评论旨在提供有关儿童实体瘤分子景观的最新技术概述，包括其潜在的基因组改变以及与微环境的相互作用，以及我们对潜在治疗漏洞的当前理解以及如何使用更准确的预测方法进行临床前测试的补充。最后，我们提供了与将这一压倒性的科学进展转化为实际的临床益处相关的挑战和机遇的前景。
更新日期：2019-11-18
中文翻译：
跨儿科实体瘤的分子特征和治疗脆弱性。
儿童时期出现的肿瘤谱与成年人所见完全不同，众所周知，它们在细胞起源，流行病学，遗传复杂性，驱动基因突变和潜在的突变过程方面与成年人的恶性肿瘤有所不同。尽管在过去十年中通过测序工作和已鉴定的（表观）遗传变异的功能表征产生了巨大的知识，但迄今为止，该知识的临床意义仍然受到限制。正在开发新型临床前平台，例如欧洲针对儿童的癌症儿科临床前概念验证创新治疗平台和美国的儿科临床前测试联盟，以试图通过概括儿童肿瘤的广泛异质性来改变这一现状。因此，希望 提高预测临床获益的能力。全球范围内也已经建立了许多研究，以使患者能够获得实时分子谱分析，并有可能基于作用机理进行更精确的治疗。除了肿瘤内在的发现和机制外，正在进行的研究还在研究诸如与成人癌症相比的儿科肿瘤的免疫微环境等特征-目前具有非常及时的临床意义。然而，持续需要严格的临床前生物标志物和靶标验证，以用于下一代分子分层的临床试验。这篇评论旨在提供有关儿童实体瘤分子景观的最新技术概述，包括其潜在的基因组改变以及与微环境的相互作用，以及我们对潜在治疗漏洞的当前理解以及如何使用更准确的预测方法进行临床前测试的补充。最后，我们提供了与将这一压倒性的科学进展转化为实际的临床益处相关的挑战和机遇的前景。
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