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

基因组表征使得能够对人类肿瘤中改变的基因进行编目，并刺激了肿瘤细胞的增殖。 开发利用这些改变的疗法。尽管如此，功能研究最终还是需要解释 并利用存在于人类癌症中的遗传变异。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著影响，因此， 有必要有体内模型，准确地概括癌症的遗传学和生理学， 患者尽管现有的基因工程小鼠模型（GEMM）有助于验证 癌症促进突变和发展的治疗概念在生理和相关的背景下，这些 模型只是太慢和昂贵，不能广泛使用，只能概括一小部分， 与人类癌症相关的遗传病变。由于需要更准确和更简单的模型， 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 三种主要上皮恶性肿瘤的基因定义小鼠模型的首次实物收集。我们称 这些模型为基于电穿孔的遗传工程小鼠模型（EPO-GEMM）。EPO-GEMM 与传统的GEMM相比具有一系列优点，因为它们是快速的、负担得起的、模块化的、高度便携的， 并且避免了与菌株互交产生的GEMM相关的大量浪费。这些模型 完全体细胞的，使灶性肿瘤的发展，重要的是，使肿瘤-宿主相互作用的研究， 允许肿瘤在不同遗传背景的宿主中快速工程化。基于大量 初步数据，以验证EPO-GEMM概念，我们的项目将产生和表征EPO-GEMM 胃癌、前列腺癌和胰腺癌--现有的小鼠模型 并不存在或者是单调乏味的。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，从测试靶点抑制的功效和毒性， 探索特定免疫细胞类型对癌症发生和发展的影响，并使用同步免疫细胞， 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- GEMM构成了“转化研究模型，这些模型是人类生物学的强大代表， 适合于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 这些模型中的一个将通过肿瘤模型保真度评分进行认证，所有试剂将 通过NCIP Hub。我们认为，快速、灵活、 和免疫活性的EPO-GEMM，并采用这些模型进行临床前研究将是至关重要的， 人类癌症遗传变异的功能注释，极大地促进了 精准肿瘤学

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.