Rapid and flexible precision oncology mouse models of epithelial malignancies epithelial malignancies

快速灵活的上皮恶性肿瘤精准肿瘤学小鼠模型

基本信息

批准号：
9886845
负责人：
SCOTT W. LOWE
金额：
$ 48.81万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886845
关键词：
Address Adoption Adult Benchmarking Biological Markers Biological Models Cancer Biology Cancer Model Cataloging Catalogs Cell Line Cell Signaling Process Cells Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Collection Combination immunotherapy Combined Modality Therapy Communities Credentialing DNA sequencing Data Dependence Development Disease Progression Electroporation Engineering Epigenetic Process Epithelial Epithelium Evaluation FGFR1 gene Flow Cytometry Genes Genetic Genetic Annotation Genetic Diseases Genetic Variation Genetically Engineered Mouse Genome Genome engineering Genomics Genotype Goals Human Human Biology Immune Immunocompetent Immunooncology Laboratories Lesion Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Methods Minor Modeling Molecular Molecular Analysis Mus Mutation Myeloid-derived suppressor cells Oncology Organ Patient-Focused Outcomes Patients Phenotype Physiological Physiology Pre-Clinical Model Property Reagent Regulatory T-Lymphocyte Role Series Testing Therapeutic Tissues Toxic effect Translational Research Treatment Protocols Tumor Suppressor Genes Tumor-infiltrating immune cells Variant Xenograft procedure anticancer research base cancer cell cancer diagnosis cancer genome cancer initiation cell type checkpoint therapy cohort efficacy testing flexibility genetic element genome sequencing host neoplasm interaction human cancer mouse model human disease human model immunoregulation in vivo in vivo Model insight malignant stomach neoplasm mouse model new therapeutic target next generation novel novel therapeutic intervention novel therapeutics portability pre-clinical precision oncology preclinical study prostate cancer model response standard of care targeted treatment therapeutic target therapy development tool transcriptome sequencing translational study tumor tumor behavior tumor microenvironment tumor progression tumorigenesis wasting whole genome

项目摘要

Genome characterization has enabled the cataloging of genes altered in human tumors and stimulated the development of therapies that exploit these alterations. Still, functional studies are ultimately needed to interpret and exploit the genetic variation that exists in human cancers. Furthermore, it is now apparent that cancer phenotypes and responses to therapy are dramatically influenced by the tissue microenvironment, and hence it is necessary to have in vivo models that accurately recapitulate both the genetics and physiology of cancers in patients. Although existing genetically engineered mouse models (GEMMs) have been instrumental in validating cancer-promoting mutations and developing therapeutic concepts in a physiological and relevant context, these models are simply too slow and expensive to be broadly useful and only recapitulate a minor fraction of the genetic lesions associated with human cancer. Driven by the need for more accurate and facile models, this project combines CRISPR genome engineering and in vivo organ electroporation with the goal of producing the first-in-kind collection of genetically-defined mouse models of three major epithelial malignancies. We refer to these models as electroporation-based genetically engineered mouse models (EPO-GEMMs). EPO-GEMMs have a range of advantages over traditional GEMMs in that they are fast, affordable, modular, highly portable, and avoid the substantial waste associated with GEMMs produced by strain intercrossing. These models are fully somatic, enable focal tumor development and, importantly, enable the study of tumor-host interactions by allowing tumors to be rapidly engineered in hosts of different genetic backgrounds. Based on substantial preliminary data to validate the EPO-GEMM concepts, our project will produce and characterize EPO-GEMMs of stomach, prostate, and pancreatic cancer - three common human cancers for which existing mouse models do not exist or are tedious. We will then perform a series of demonstration projects to evaluate and illustrate the unique potential of the EPO-GEMM approach, ranging from testing the efficacy and toxicity of target inhibition, exploring the effects of specific immune cell types on cancer initiation and progression, and using synchronous cohorts of genetically defined cancer models to test new targeted therapies and immune oncology approaches. Therefore, our project is of direct relevance to the overarching goals of the Oncology Models Forum, as EPO- GEMMs constitute “translational research models that are robust representations of human biology, are appropriate to test questions of clinical importance, and provide reliable information for patients’ benefit”. Each of these models will be credentialed with the Oncology Model Fidelity Score and all reagents will be made available through the NCIP Hub. We believe that the development and detailed characterization of rapid, flexible, and immunocompetent EPO-GEMMs and the adoption of these models for pre-clinical studies will be critical for the functional annotation of genetic variation in human cancer and greatly contribute to the implementation of precision oncology.

基因组表征使人类肿瘤中的基因编目成为可能，并刺激了开发利用这些改变的疗法仍然需要功能研究来解释。并利用人类癌症中存在的遗传变异。此外，现在很明显癌症。表型和对治疗的反应受到组织微环境的显着影响，因此有必要拥有能够准确重现癌症遗传学和生理学的体内模型尽管现有的基因工程小鼠模型（GEMM）在验证方面发挥了重要作用。促进癌症的突变并在生理和相关背景下开发治疗概念，这些模型太慢且昂贵，无法广泛使用，并且只能概括一小部分由于需要更准确、更简便的模型，这导致了与人类癌症相关的遗传病变。该项目结合了 CRISPR 基因组工程和体内器官电穿孔，目标是生产我们指的是三种主要上皮恶性肿瘤的基因定义小鼠模型的首个集合。这些模型作为基于电穿孔的基因工程小鼠模型（EPO-GEMM）。与传统 GEMM 相比，它们具有一系列优势，因为它们速度快、价格实惠、模块化、高度便携、并避免与菌株交叉产生的 GEMM 相关的大量浪费。完全体细胞，能够实现局灶性肿瘤的发展，重要的是，能够通过以下方式研究肿瘤与宿主的相互作用：允许在不同遗传背景的宿主中快速改造肿瘤。验证 EPO-GEMM 概念的初步数据，我们的项目将生产并表征 EPO-GEMM 胃癌、前列腺癌和胰腺癌——现有小鼠模型所针对的三种常见人类癌症然后，我们将执行一系列演示项目来评估和说明。 EPO-GEMM 方法的独特潜力，包括测试靶标抑制的功效和毒性，探索特定免疫细胞类型对癌症发生和进展的影响，并使用同步一组基因定义的癌症模型，用于测试新的靶向疗法和免疫肿瘤学方法。因此，我们的项目与肿瘤模型论坛的总体目标直接相关，因为 EPO- GEMM 构成“转化研究模型，是人类生物学的有力代表，是适合测试具有临床重要性的问题，并为患者的利益提供可靠的信息”。这些模型中的一些将获得肿瘤模型保真度评分的认证，并且所有试剂都将被制造我们相信，可以通过 NCIP 中心进行快速、灵活的开发和详细表征。和免疫活性 EPO-GEMM 以及采用这些模型进行临床前研究对于人类癌症遗传变异的功能注释，并极大地促进了精准肿瘤学。