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Core 3: Preclinical Models and Therapeutics Core

核心 3：临床前模型和治疗核心

基本信息

批准号：
10153728
负责人：
Giorgio Inghirami
金额：
$ 25.98万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153728
关键词：
3-Dimensional Animals Architecture Biological Biological Assay Cancer Model Cell Line Chromatin Clinical Collaborations Complex Data Databases Defect Dissection Engineering Experimental Leukemia Fingerprint Fostering Funding Gene Expression Regulation Genes Genetic Genetic Transcription Genome Genomics Human Immunocompromised Host In Vitro Knowledge Lesion Lymphoma Malignant Neoplasms Mission Modeling Molecular Mus Mutate Oncogenic Organoids Pathogenicity Pathologic Pathology Patients Pharmaceutical Preparations Phenotype Play Pre-Clinical Model Preclinical Testing Public Health Reagent Research Research Personnel Resources Role Sampling Services System Technology Testing Therapeutic Tissue Sample Transgenic Mice Tumor-Derived Xenograft Model base design established cell line human tissue in vitro activity in vivo innovation large cell Diffuse non-Hodgkin&apos s lymphoma mouse model patient derived xenograft model predicting response predictive marker programs targeted treatment three dimensional cell culture translational cancer research tumor tumor heterogeneity tumor progression tumor xenograft web site

项目摘要

SUMMARY – PATHOLOGY CORE The Pathology Core (PC) will assemble and characterize the reagents critical for this proposal including the wide array of engineered mouse models, clinically and molecularly annotated primary samples, patient derived tumor xenograft (PDTX) models as well as patient derived organoids (PDOs). These resources will be provided to project leaders to cross validate experimental findings, define the pathogenetic role of defined lesions and identify their relevance in human tissue samples using PDTX and PDO models. We anticipate that the services of the PC core will provide the basis for the biological dissection of the genetic lesions described in all three Projects, leading to a deeper knowledge of how 3D genome organization plays a crucial role in gene regulation, oncogenic transcriptional programs and the design of more efficient therapeutic approaches. Translational cancer research has been greatly facilitated by the demonstration that defined genomic defects are associated with unique functional fingerprints which can be effectively validated in vitro using primary 2D and 3D cultures and by employing innovative transgenic mouse models and tumor xenografts in immunocompromised mice. Importantly, primary 2D and 3D cultures and tumor xenografts have been tested showing that they largely mimic the original patient tumor, including tumor heterogeneity and can effectively predict response to therapies. Of note, models from primary patient derived cultures or PDTX have proven to be more informative than conventional cells lines allowing precise determinations and more reliable assessments. Lastly, as many as 85% of drugs with in vitro activity in established cell lines have failed in human studies, primarily because of a lack of efficacy in complex systems or in human settings. Thus, our models are particularly useful for in vivo mechanistic studies (Projects 1-3), and the information they provide will be instrumental in understanding the pathogenic potential of the defects investigated in this application, leading to potential targeted therapies (Projects 2 and 3).

总结——病理学核心病理学核心 (PC) 将组装和表征对该提案至关重要的试剂，包括广泛的工程小鼠模型、临床和分子注释的原始样本、源自患者的肿瘤异种移植（PDTX）模型以及患者来源的类器官（PDO）。将提供这些资源项目负责人交叉验证实验结果，定义特定病变的致病作用和使用 PDTX 和 PDO 模型确定它们在人体组织样本中的相关性。我们预计服务 PC 核心的研究将为所有三个中描述的遗传病变的生物解剖提供基础项目，让您更深入地了解 3D 基因组组织如何在基因中发挥关键作用调控、致癌转录程序和更有效的治疗方法的设计。基因组缺陷的定义极大地促进了转化癌症研究与独特的功能指纹相关，可以使用初级 2D 在体外进行有效验证和 3D 培养，并通过采用创新的转基因小鼠模型和肿瘤异种移植物免疫功能低下的小鼠。重要的是，原代 2D 和 3D 培养物以及肿瘤异种移植物已经过测试表明它们在很大程度上模仿了原始患者肿瘤，包括肿瘤异质性，并且可以有效地预测对治疗的反应。值得注意的是，来自原代患者的培养物或 PDTX 的模型已被证明可以比传统细胞系提供更多信息，可以进行精确的测定并且更可靠评估。最后，多达 85% 在已建立的细胞系中具有体外活性的药物在体外试验中失败了。人类研究，主要是因为在复杂系统或人类环境中缺乏功效。因此，我们的模型对于体内机制研究（项目 1-3）特别有用，并且它们提供的信息将有助于了解本应用中研究的缺陷的致病潜力，导致潜在的靶向治疗（项目 2 和 3）。