eDyNAmiC - SCRIPPS

动态 - 斯克里普斯

• 批准号: 10625797
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 33.23万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-24 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625797
• 关键词: Text

eDyNAmiC (extrachromosomal DNA in Cancer) Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumour-promoting genes can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal “rules” of chromosomal inheritance, enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible, and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed, further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago, the critical importance of ecDNA has only recently come to light, and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form, how they function, how they move around the cell, how they evolve to resist treatment, how they impact the immune system, and how they can be effectively targeted are lacking. We bring together an internationally recognized, pioneering interdisciplinary team of cancer biologists, geneticists, computer scientists, evolutionary biologists, mathematicians, clinicians, and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancer’s Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics, yeast genetics, epigenomics, artificial genome synthesis, longitudinal patient tracking, combinatorial and machine learning algorithms, mathematical modelling, immunobiology, and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer, and we will find new ways to drug the undruggable. This bold programme, which consists of 7 work packages and a committed international infrastructure, generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients.

eDyNAmiC（癌症中的染色体外 DNA） 人类基因排列在 23 对染色体上，但在癌症中，促肿瘤基因可以从染色体中释放出来，并重新定位到环状的染色体外 DNA 片段 (ecDNA)，这些 ecDNA 不遵循染色体遗传的正常“规则”。使肿瘤能够获得比其他方式更高水平的致癌基因，并许可癌症以一种进化和改变其基因组的方式来逃避治疗对于人类细胞来说，改变的环状结构也改变了致癌基因的调节和表达方式，进一步促进了侵袭性肿瘤的生长，这些独特的特征使得含有 ecDNA 的癌症特别具有侵袭性且难以治疗。肿瘤中含有 ecDNA 的癌症患者的生存期明显较短，尽管 ecDNA 的重要性在五十多年前才被发现，但直到最近才被人们认识到，而且问题的严重性是巨大的。 ecDNA 存在于近一半的人类癌症类型中，可能存在多达三分之一的癌症患者。目前对 ecDNA 如何形成、它们如何发挥作用、它们如何在细胞中移动、它们如何进化以抵抗治疗的集体了解我们汇集了国际公认的、由癌症生物学家、遗传学家、计算机科学家、进化生物学家、数学家、主教和患者倡导者组成的开拓性跨学科团队，以大胆地创造新的药物。见解和资源一个由经验丰富、富有成效的 ecDNA 研究人员组成的核心团队将与 ecDNA 和癌症领域的新研究人员合作，通过桥接尖端和多样化的解决方案，为这一艰巨的挑战带来全新的视角和方法。来自癌症基因组学、酵母遗传学、表观基因组学、人工基因组合成、纵向患者追踪、组合和机器学习算法、数学建模、免疫生物学和创新化学的方法和见解，我们将对 ecDNA 的作用产生新的理解这个大胆的计划由 7 个工作包和一个坚定的国际基础设施组成，将产生新的、不寻常的合作，这在我们的计划中是任何其他类型的资助机制都不可能实现的。努力针对癌症中最棘手的问题之一和癌症患者面临的最大挑战之一提出大胆的创新解决方案。