Core C: Animal Modeling and Preclinical Therapeutics

P01中的动物建模和临床前治疗核心将使用基因工程小鼠(GEM) 肺癌模型、标准肺癌细胞系异种移植和患者来源的肺癌异种移植 (PDX)，以便于识别最有效的工具化合物和化合物组合(S) 在每个项目中研究的特定基因分层型肺癌的治疗。这个核心将 为计划中的每个项目提供活体实验的技术和科学专业知识，并允许 三个项目中每个项目的集体努力，以更多地侧重于机械研究，以确定最佳 化合物的组合以最大限度地发挥治疗效果。 基于特定致癌基因改变的肺癌GEM模型在 进一步加深对肺癌发病机制的分子机制的认识 开发有效的特定类型癌基因驱动的肺癌的靶向治疗方法。我们的 实验室已经产生并鉴定了30多个条件转基因小鼠的等位基因，这些等位基因具有诱导性 每种特征性肺癌相关致癌驱动因素的表达。我们还创建了一个 超过50个基因注释的非小细胞肺癌细胞系的库，可用于传统的异种移植 学习。更重要的是，这些GEM和标准的异种移植肺癌模型已经被采用。 以基因为靶点的新疗法在多种疗效和药效学研究中取得成功 明确的致癌驱动因素或其下游效应通路。此外，我们的实验室正在进行 从患者切除/活检样本中获得的肺癌PDX模型的生成和特征 DFCI。合适的EGFR、KRAS和其他特定基因型的GEM、PDX和异种移植模型将 用于本P01建议书中描述的每个项目。 总体而言，动物建模和临床前治疗核心将促进临床前发现 实现临床翻译，最终目标是改善肺癌的预后。

Animal Modeling and Preclinical Therapeutics Core in this P01 will use genetically engineered mouse (GEM) models of lung cancer, standard lung cancer cell line xenografts, and patient-derived lung cancer xenografts (PDXs) to facilitate the identification of the most effective tool compounds and combination(s) of compounds in the treatment of the genotype-specific stratified lung cancers studied in each of the projects. This core will provide technical and scientific expertise for in vivo experiments for each project in the program and allow the collective efforts of each of the three projects to focus more on the mechanistic studies to identify the best combination of compounds to maximize therapeutic efficacy. GEM models of lung cancers based on specific oncogenic genetic alterations have been instrumental in advancing the understanding of the molecular mechanisms of lung cancer pathogenesis and in the development of targeted therapeutics that are effective specific types of oncogene-driven lung cancer. Our laboratory has generated and characterized well over 30 conditional transgenic mice alleles that have inducible expression of each of the characterized lung cancer relevant oncogenic drivers. We have also created a repository of over 50 genomically annotated NSCLC lines, which can be used for conventional xenograft studies. More importantly, these GEM and standard xenograft lung cancer models have been employed successfully in multiple efficacy and pharmacodynamics studies with novel therapeutics that target genetically defined oncogenic drivers or their downstream effector pathways. In addition, our laboratory are in the process of generating and characterizing lung cancer PDX models derived from patient resected/biopsy samples at DFCI. The appropriate EGFR, KRAS, and other-genotype specific GEM, PDX and xenograft models will be used for each of the projects described in this P01 proposal. Overall the Animal Modeling and Preclinical Therapeutics Core will facilitate the preclinical discoveries that enable clinical translation with the ultimate goal of improving lung cancer outcomes.