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

尽管有数百个临床试验和我们对遗传学的理解的巨大进步， 以及该疾病的分子生物学，患有胶质母细胞瘤的患者的中位生存期 从30年前的12个月变成了现在的15个月。难怪少数人 这些年来我治疗过的大约有两万名神经胶质瘤患者仍然活着。显然是一种新的方式 了解和治疗这种疾病是必要的。在这个建议中，我假设一个主要的 神经胶质瘤缺乏成功治疗的原因是未能模拟神经胶质瘤的复杂性， 以及由此产生的“癌症状态”的涌现特性。我们能够全面 了解并最终治疗操纵复杂的癌症表型， 需要建立临床相关模型， 复杂性考虑到这些参数不符合任何当前的模型系统， 这项建议的目的是通过建立一个模型， 第一次将使我们能够在实验室中研究GBM作为人类疾病。 为此，我们建议建立一个人类大脑的体外模型， 以患者特有的方式治疗肿瘤。我们已经实现了这一倡议的第一次迭代， 成功地产生从人胚胎干细胞产生的人脑类器官 系和来自患者特异性诱导多能干细胞。这些大脑类器官 几乎所有的正确的细胞类型和正确定向的神经解剖隔间， 一个20周的人类胎儿大脑此外，原代患者来源的GBM干细胞生长 并形成破坏性肿瘤， 亲代临床肿瘤同样，我们可以通过引入基因组DNA来形成从头GBM。 通过使用先进的技术， 基因编辑技术 我现在提出，大脑类器官，或患者衍生的“迷你脑”，提供了一个独特的， 通过在体外创建复杂的“肿瘤系统”来研究GBM的新模型系统， 概括了肿瘤生长的体内条件， 生物学（临床）相关，逻辑上务实和科学严谨的方式。这 这种方法将使我们第一次机械地研究临床上明显的紧急情况， GBM的现象，以前没有研究，最终导致新的和更有效的 战略治疗方法来对付这种毁灭性的疾病。

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.