Human Brain Cancer, Rather than Brain Cancer Cells, on a Plate

盘子里的是人脑癌，而不是脑癌细胞

• 批准号: 10251121
• 负责人: Howard A Fine
• 金额: $ 118.65万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251121
• 关键词: Anatomy; Autologous; Biological; Biological Models; Brain; Brain Neoplasms; Caring; Cerebrum; Clinical; Clinical Trials; Complex; Disease; Failure; Genes; Genetic; Glioblastoma; Glioma; Human; In Vitro; Laboratories; Logistics; Malignant Neoplasms; Malignant neoplasm of brain; Methods; Modeling; Molecular Biology; Organoids; Patients; Phenocopy; Phenotype; Property; System; Techniques; Therapeutic; Time; anticancer research; cancer cell; cell type; clinically relevant; effective therapy; genomic aberrations; human disease; human embryonic stem cell line; human fetal brain; in vitro Model; in vivo; induced pluripotent stem cell; novel; novel strategies; personalized medicine; personalized screening; stem cells; tumor; tumor growth

Despite hundreds of clinical trials and dramatic advances in our understanding of the genetics and molecular biology of the disease, the median survival of patients suffering with glioblastoma has gone from 12 months three decades ago to 15 months today. No wonder that few of the roughly 20,000 glioma patients I have cared for over the years are still alive. Clearly a new way to understand and approach this disease is needed. In this proposal I hypothesize that a major reason for the lack of successful therapies in gliomas is a failure to model the complexity and resulting emergent properties of the “cancer state”. Our ability to comprehensively understand and ultimately therapeutically manipulate complex cancer phenotypes will require the creation of clinically relevant models that intrinsically embrace that complexity. Given that these parameters are not met by any current model system, it is the intent of this proposal to take a novel approach to cancer research by building a model that for the first time will allow us to study GBM in the laboratory as the human disease that it is. To that end we propose building an in vitro model of the human brain harboring a growing tumor in a patient-specific manner. We have achieved the first iteration of this initiative by successfully generating human cerebral organoids generated from human embryonic stem cell lines and from patient-specific induced pluripotent stem cells. These cerebral organoids have almost all of the correct cell types and correctly oriented neuro-anatomic compartments seen in a 20-weeks of human fetal brain. Moreover, primary patient-derived GBM stem cells grow within their autologous cerebral organoids and form destructive tumors that phenocopy the parental clinical tumor. Likewise, we can form de novo GBMs by introducing genomic aberrations of the patient's original tumor within their own cerebral organoids by using advanced gene editing techniques. I now propose that cerebral organoids, or patient derived “minibrains,” offer a unique and novel model system for studying GBM by creating a complex “tumor system” in vitro that largely recapitulates in vivo conditions of tumor growth but in an experimentally manipulable, biologically (clinically) relevant, logistically pragmatic and scientifically rigorous way. This approach will allow us for the first time to mechanistically study clinically apparent emergent phenomenon of GBM, not previously studied, ultimately leading to novel and more effective strategic therapeutic approaches to this devastating disease.

尽管数百项临床试验和我们对遗传学的理解取得了戏剧性的进步 与疾病的分子生物学有关，胶质母细胞瘤患者的中位生存期 已经从30年前的12个月增加到今天的15个月。难怪有那么几个 多年来，我照顾过的大约2万名胶质瘤患者仍然健在。显然是一种新的方式 了解和处理这种疾病是必要的。在这项提议中，我假设一名少校 胶质瘤缺乏成功治疗的原因是未能对复杂性进行建模 以及由此产生的“癌症状态”的紧急性质。我们有能力全面 理解并最终在治疗上操纵复杂的癌症表型将 需要创建与临床相关的模型，从本质上包含这一点 复杂性。鉴于当前任何模型系统都不满足这些参数，它是 这项提议的目的是通过建立一个模型来采用一种新的方法来研究癌症 第一次将使我们能够在实验室中将GBM作为人类疾病进行研究。 为此，我们建议建立一个人类大脑的体外模型，该模型含有不断增长的 以特定于患者的方式治疗肿瘤。我们通过以下方式实现了这一倡议的第一次迭代 人胚胎干细胞成功生成人脑器官 来自患者特异性诱导的多能干细胞。这些大脑器官有 几乎所有正确的细胞类型和正确定位的神经解剖隔间在 一个长达20周的人类胎儿大脑。此外，原代患者来源的GBM干细胞可以生长 在它们的自体脑器官内形成破坏性的肿瘤，这种肿瘤的表型 亲代临床肿瘤。同样，我们可以通过引入基因组来形成从头开始的GBM 应用先进的计算机辅助技术治疗患者原发瘤在其自身脑器官内的畸变 基因编辑技术。 我现在建议大脑器官，或患者来源的“迷你大脑”，提供了一种独特的 通过在体外建立复杂的肿瘤系统来研究基底膜的新模型系统 概述了体内肿瘤生长的条件，但在实验可操作的情况下， 生物学上(临床上)相关，逻辑上务实，科学上严谨。这 这种方法将使我们第一次能够机械地研究临床明显的紧急情况 GBM现象，以前没有研究过，最终导致了新的和更有效的 针对这一毁灭性疾病的战略治疗方法。