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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：
10402277
负责人：
Giorgio Inghirami
金额：
$ 28.3万
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/10402277
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 treatment response 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).

摘要-病理学核心病理学核心(PC)将组装和描述对该提案至关重要的试剂，包括广泛的工程化小鼠模型，临床和分子注释的初级样本，患者来源肿瘤异种移植(PDTX)模型以及患者来源的有机化合物(PDO)。这些资源将被提供项目负责人交叉验证实验结果，定义已定义病变的致病作用，并使用PDTX和PDO模型确定它们在人体组织样本中的相关性。我们预计这些服务将为对所有三种基因损伤进行生物解剖提供基础项目，使人们更深入地了解3D基因组组织如何在基因中发挥关键作用监管、致癌转录程序和设计更有效的治疗方法。定义基因组缺陷的证明极大地促进了转化性癌症的研究与独特的功能指纹相关联，这些指纹可以在体外使用初级2D有效验证和3D培养，并使用创新的转基因小鼠模型和肿瘤移植在免疫功能低下的小鼠。重要的是，2D和3D原代培养和肿瘤异种移植已经过测试表明它们在很大程度上模仿了原始患者的肿瘤，包括肿瘤的异质性，并可以有效地预测对治疗的反应。值得注意的是，来自原发患者衍生培养或PDTX的模型已经证明比传统的细胞系提供更多的信息，从而允许精确的测定和更可靠的评估。最后，在已建立的细胞系中具有体外活性的药物中，多达85%的药物在人体研究，主要是因为在复杂的系统或人类环境中缺乏效力。因此，我们的模型对于活体机制研究(项目1-3)及其提供的信息特别有用将有助于理解在本申请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)。