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Core C: Animal Modeling and Preclinical Therapeutics

核心 C：动物建模和临床前治疗

基本信息

批准号：
10231104
负责人：
Kwok Kin Wong
金额：
$ 26.38万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-11 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231104
关键词：
Alleles Animal Model Animals Biopsy Specimen Cancer Model Cancer Patient Cancer cell line Chronic Collaborations Development Diagnosis Emission-Computed Tomography Epidermal Growth Factor Receptor Funding Generations Genetically Engineered Mouse Genotype Goals Human Imaging technology In Vitro Infrastructure Intervention Studies Investigational Therapies Joints KRAS2 gene Laboratories Magnetic Resonance Imaging Malignant neoplasm of lung Modeling Molecular Mus Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Outcome Pathogenesis Pathway interactions Patients Pharmacodynamics Procedures Process Protein Kinase Publications Quality Control Relapse Research Research Personnel Resected Resistance Resources Standardization Therapeutic Therapeutic Intervention Therapeutic Studies Time Transgenic Mice Treatment Efficacy X-Ray Computed Tomography Xenograft Model Xenograft procedure base clinical translation cost efficacy study experience experimental study improved in vivo in vivo Model inducible gene expression innovation lung cancer cell lung xenograft microPET mouse model new therapeutic target non-invasive imaging novel therapeutics patient derived xenograft model pre-clinical programs repository small molecule inhibitor targeted treatment therapeutic target therapeutically effective tool

项目摘要

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.

本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物和患者来源的肺癌异种移植物（PDX），以促进在药物组合物中鉴定最有效的工具化合物和化合物的组合。在每个项目中研究的基因型特异性分层肺癌的治疗。核心将为该计划中的每个项目提供体内实验的技术和科学专业知识，并允许这三个项目中的每一个项目的集体努力，更多地侧重于机制研究，以确定最佳的化合物的组合以最大化治疗功效。基于特定致癌基因改变的肺癌GEM模型有助于促进对肺癌发病机制的分子机制的理解，开发有效的特定类型的癌基因驱动的肺癌的靶向治疗剂。我们一个实验室已经产生并表征了超过30种条件性转基因小鼠等位基因，每个表征的肺癌相关致癌驱动因子的表达。我们还创建了一个超过50个基因组注释的NSCLC细胞系的库，其可用于常规异种移植问题研究更重要的是，这些GEM和标准异种移植肺癌模型已被采用成功地在多个功效和药效学研究中使用靶向遗传的新疗法，定义致癌驱动或其下游效应途径。此外，我们的实验室正在产生和表征源自患者切除/活检样本的肺癌PDX模型， DFCI。适当的EGFR、KRAS和其他基因型特异性GEM、PDX和异种移植物模型将在用于本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，实现临床转化，最终目标是改善肺癌预后。