cliniCIN: Targeting the roots of chromosomal instability in cancer

cliniCIN：针对癌症染色体不稳定的根源

• 批准号: EP/X028054/1
• 负责人: Florian Markowetz
• 金额: $ 274.5万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX028054%2F1
• 关键词: cliniCIN; Targeting; roots; chromosomal; instability

GOAL: Overcoming the genomic complexity of cancers with high chromosomal instability by using signatures of ongoing mutational processes as biomarkers for drug response.BACKGROUND: Chromosomal instability is a hallmark of most lethal cancers. Highly unstable tumours have few biomarkers to guide treatment decisions and patient survival has not improved for decades. My team pioneered approaches to dissect chromosomal instability using genome-wide DNA copy number patterns, so called CIN signatures, which are characteristic for different types of instability and underlying mutational processes. In pilot studies we found that CIN signatures predict drug response. Signature analysis focuses on the cause, rather than the consequence of chromosomal instability, and thus represents a radical departure from previous personalised medicine approaches. APPROACH: Here, I am building on genomic and computational technologies I have developed to design biomarkers for treating cancers with high chromosomal instability. I propose a novel single cell DNA sequencing approach to identify ongoing mutational processes from unique events in individual cells. This pharmacogenomic test is a major advance, because it allows to separate ongoing mutational processes, which are actively contributing to cancer development, from extinct mutational processes, which left marks in the genome but are no longer active. I will systematically identify robust and predictive biomarkers of drug response in a comprehensive experimental plan across five highly unstable cancers (esophageal, lung, pancreatic, ovarian and triple negative breast cancer) and measure the heterogeneity of CIN across tumour microenvironments in patients undergoing neo-adjuvant treatment. IMPACT: This pioneering project will result in fundamental insights into how cancers with different types of chromosomal instability react to drugs and how to exploit genomic complexity for patient benefit in cancers of unmet clinical need.

目标：通过使用正在进行的突变过程的签名作为药物反应的生物标志物，克服具有较高染色体不稳定的癌症的基因组复杂性。BACKCOUND：染色体不稳定性是大多数致命癌症的标志。高度不稳定的肿瘤几乎没有生物标志物来指导治疗决策，而且患者的生存数十年来一直没有改善。我的团队开创了使用全基因组DNA拷贝数模式（所谓的CIN签名）剖析染色体不稳定性的方法，这是不同类型的不稳定性和潜在突变过程的特征。在试点研究中，我们发现CIN特征可以预测药物反应。签名分析的重点是原因，而不是染色体不稳定性的后果，因此代表了与以前的个性化医学方法的根本性不同。方法：在这里，我正在建立基于基因组和计算技术的基础，该技术是为了设计用于治疗高染色体不稳定性癌症的生物标志物。我提出了一种新型的单细胞DNA测序方法，以从单个细胞中的独特事件中识别正在进行的突变过程。该药物基因组学测试是一个重大进步，因为它允许将正在进行的突变过程分开，这些突变过程正在积极地促进癌症发展，而灭绝的突变过程，这些突变过程在基因组中留下了标记，但不再活跃。我将在五种高度不稳定的癌症（食管，肺，胰腺，胰腺，卵巢癌和三重阴性乳腺癌）中，系统地确定药物反应的强大和预测性生物标志物，并测量跨肿瘤微环境的CIN的异质性治疗。影响：这个开创性的项目将导致对具有不同类型的染色体不稳定性癌症的癌症如何反应药物以及如何利用基因组复杂性以使患者受益于未满足的临床需求的癌症中的利益。