Core 2: Human Specimen and Organic Core (HSO Core)

项目摘要-核心2：人体标本和有机物质核心 被诊断为胰腺导管腺癌(PDA)的患者往往对治疗干预无效。 或迅速对治疗产生抗药性。为了研究药物耐药的机制，组装了P01 研究小组将利用大量具有代表性的PDA患者衍生的三维器官类物质 型号(PDO)。有机化合物准确地概括了基因组、转录和表型特征 并能够在不同的患者队列中预测药物反应。《人类》 标本和有机物核心(HSO核心)将有助于阐明抗药性的机制 与每个研究项目进行协作。HSO核心将测试许多新的治疗组合 确定有效和协同的战略。核心将提供一个强大的患者衍生的器官型 用于体外机制研究的肿瘤切片平台。此外，HSO核心将产生有机化合物共培养 并将从基因工程小鼠(GEM)模型中开发出有机化合物 自发性掌上电脑。HSO核心的总体目标是支持每个项目的发现和验证 有效的治疗策略，以克服治疗耐药性。要做到这一点，HSO核心有三个 目标。在目标1中，核心将提供为每个目标量身定做的方法专业知识和宝贵的PDO模型 个人项目。新的治疗组合，包括内抑素(项目1)和ULK1/2等药物 抑制剂(项目3)将使用药物分型试验进行分析，这将利用Core的 不同种类的有机化合物。将对组合进行评估，并对协同效应进行数学定义。 将利用现有的DNA/RNA测序数据集来发现药物敏感性的预测特征 和抵抗。在目标2中，核心将提供对器官型活肿瘤切片模型的访问，该模型保存了 PDA的肿瘤性和间质细胞室。HSO核心开发的方法允许 体外培养长达7天，使细胞到细胞信号网络的扰动和表征成为可能。 此外，Core将开发包含上皮类器官、成纤维细胞和免疫的联合培养系统 与项目协作的单元2。最后，在目标3中，核心将与鼠标模型核心协作，以 从以前不可用的宝石模型中生成鼠标衍生的有机化合物，并开发有机化合物资源 促进研究项目和核心的工作流程。

PROJECT SUMMARY – Core 2: Human Specimen and Organoid Core Patients diagnosed with pancreatic ductal adenocarcinoma (PDA) often fail to respond to therapeutic intervention or rapidly develop resistance to treatment. To study mechanisms of therapeutic resistance, the assembled P01 research team will utilize a large and representative cohort of PDA patient-derived three-dimensional organoid models (PDOs). Organoids accurately recapitulate the genomic, transcriptomic, and phenotypic characteristics of human PDA and enable predictive profiling of drug response in a heterogenous patient-cohort. The Human Specimen and Organoid Core (HSO Core) will facilitate the elucidation of mechanisms of resistance in collaboration with each Research Project. The HSO Core will test numerous novel therapeutic combinations to determine effective and synergistic strategies. The Core will provide a powerful patient-derived organotypic tumor slice platform for ex vivo mechanistic studies. In addition, the HSO Core will generate organoid co-cultures with key stromal cells and will develop organoids from genetically engineered mouse (GEM) models that develop spontaneous PDA. The overall goal of the HSO Core is to support each Project in the discovery and validation of effective therapeutic strategies to overcome treatment resistance. To accomplish this, the HSO Core has three Aims. In Aim 1, The Core will provide methodology expertise and valuable PDO models tailored to each individual Project. Novel therapeutic combinations that include drugs such as Entinostat (Project 1) and ULK1/2 inhibitors (Project 3) will be profiled using a pharmacotyping assay that takes advantage of the Core’s heterogenous cohort of organoids. Combinations will be evaluated and synergies mathematically defined. Existing DNA/RNA-sequencing datasets will be leveraged to discover predictive signatures of drug sensitivity and resistance. In Aim 2, the Core will provide access to an organotypic living tumor slice model that preserves the neoplastic and stromal cellular compartments of PDA. Methodologies developed by the HSO Core allow for ex vivo culture up to 7 days, enabling the perturbation and characterization of cell to cell signaling networks. Further, the Core will develop co-culture systems that incorporate epithelial organoids, fibroblasts, and immune cells in collaboration with Projects 2. Finally in Aim 3, the Core will collaborate with the Mouse Models Core to generate mouse-derived organoids from previously unavailable GEM models and develop organoid resources to facilitate the workflow of the Research Projects and Cores.