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

基因组特征使人类肿瘤中改变的基因得以编目，并刺激了 开发利用这些变化的治疗方法。然而，最终还是需要功能研究来解释 并利用存在于人类癌症中的基因变异。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著影响，因此 有必要建立体内模型，准确地概括癌症的遗传学和生理学 病人。尽管现有的基因工程小鼠模型(GEMM)在验证 促进癌症的突变和在生理和相关背景下发展治疗概念，这些 模型太慢太贵，不能广泛使用，而且只概括了 与人类癌症相关的基因损伤。由于对更准确和更方便的模型的需求，这 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 首次收集了三种主要上皮性恶性肿瘤的基因定义的小鼠模型。我们指的是 这些模型被称为基于电穿孔的基因工程小鼠模型(EPO-GEMM)。EPO-GEMM 与传统的GEM相比，具有一系列优势，因为它们快速、负担得起、模块化、高度便携、 并避免与通过品系杂交产生的转基因材料相关的大量浪费。这些型号是 完全体细胞，使局部肿瘤发展，更重要的是，通过以下方式研究肿瘤-宿主相互作用 这使得肿瘤可以在不同遗传背景的宿主中快速培育出来。基于大量的 初步数据为了验证EPO-GEMM的概念，我们的项目将生产和表征EPO-GEMM 胃癌、前列腺癌和胰腺癌--三种常见的人类癌症--现有的小鼠模型 不存在或令人厌烦。然后，我们将执行一系列示范项目，以评估和说明 EPO-GEMM方法的独特潜力，从测试靶标抑制的有效性和毒性， 探索特定免疫细胞类型对癌症发生和发展的影响，并使用同步 基因定义的癌症模型队列，以测试新的靶向治疗和免疫肿瘤学方法。 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- 基因工程模型构成了“翻译研究模型，这些模型是人类生物学的强健代表，是 适当地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。每个人 在这些模型中，将获得肿瘤学模型保真度分数的认证，所有试剂将 可通过NCIP中心获得。我们相信，快速、灵活、 和免疫活性EPO-GEMM以及将这些模型用于临床前研究将是至关重要的 对人类癌症基因变异的功能诠释，有助于实现 精确肿瘤学。

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.