Epigenetically Engineered Mouse Model for Lung Cancer Therapy

用于肺癌治疗的表观遗传工程小鼠模型

基本信息

批准号：
10272375
负责人：
Lanlan Shen
金额：
$ 36.53万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10272375
关键词：
Aberrant DNA Methylation Adenocarcinoma Affect Alleles Animal Model Benign Biological Models Cancer Model Cancer Patient Cancer Prognosis Cell Communication Cell Cycle Regulation Cell physiology Cells Communities Complex Cyclin-Dependent Kinase Inhibitor 2A DNA Methylation DNA Methyltransferase Inhibitor DNA Sequence Alteration Development Disease Drug Targeting Engineering Epigenetic Process Epithelial Etiology Event Gene Mutation Gene Silencing Gene Targeting Genes Genetic Genetically Engineered Mouse Goals HDAC4 gene Heritability Histone Deacetylase Inhibitor Human Immunocompetent Immunotherapy Intervention KRAS2 gene Laboratories Lead Lentivirus Vector Lesion Link Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Methylation Mitotic Modeling Molecular Monitor Mus Mutation Neoplasm Metastasis Non-Malignant Oncogenic Organoids Pathway interactions Pattern Phenotype Prevention Public Health Publishing Regulator Genes Research Research Project Grants Role Stress Survival Rate System Testing Therapeutic Translational Research Tumor Suppressor Genes Work anti-PD-L1 anticancer research base cancer initiation cancer prevention cancer therapy clinically relevant combinatorial epigenetic silencing epigenetic therapy gene function human model immune checkpoint improved in vivo insight lung development lung tumorigenesis malignant phenotype mouse model mutant novel organoid transplantation programmed cell death ligand 1 promoter response senescence single-cell RNA sequencing targeted treatment transcriptome sequencing translational model tumor tumor growth tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY (Abstract) The importance of aberrant DNA methylation in cancer is clear. The fundamental role of DNA methylation in cancer initiation and progression, however, remains elusive. The use of gene targeting in animal models definitively demonstrated that genetic mutations at specific genes cause disease. An analogous “epigenetic gene targeting” approach is urgently needed to advance the field of epigenetics. In human lung cancers, p16 promoter methylation associated epigenetic silencing is one of the earliest detected epimutations and is thought to function as a critical initiating event in tumorigenesis. The importance of this epimutation is further underscored by the associations with distinct gene mutation patterns, cancer prognosis, and response to therapy. However, the molecular pathways linking aberrant DNA methylation, epigenetic silencing, and tumorigenesis remain poorly characterized. In this regard, we published the first mouse model demonstrating that targeted p16 epimutation drives spontaneous tumor development. Importantly, our preliminary studies revealed that p16 epimutation operates synergistically with oncogenic K-RAS activation to drive lung cancer progression. Based on these findings, this proposal responds to PAR-20-131: Research Projects to Enhance Applicability of Mammalian Models for Translational Research. Our overall goals are to establish more faithful murine models of human lung cancer development and to utilize this epigenetically engineered mouse model for testing novel epigenetic therapeutic strategies. Specifically, we will: 1 − Employing epigenetic engineering in mice to model advanced human lung cancers. We propose to establish clinically relevant and immunocompetent mouse models based on defined genetic and epigenetic alterations to drive benign lung tumor growths towards the ultimate malignant phenotype. 2 − Testing combinatorial epigenetic therapy in mouse lung tumors carrying a driver p16 epimutation. We propose to test whether epigenetic targeting drugs and/or anti-PD-L1 immunotherapy can effectively suppress p16 epimutant lung tumor growth during critical transition points from non-malignant lesions to adenocarcinoma. These studies will elucidate the functional role of epimutations in lung tumorigenesis in vivo. Successful completion of the proposed studies will provide a mechanistic rationale to refine ongoing epigenetic therapy, with the potential to improve survival rates in lung cancer.

项目概要（摘要）异常 DNA 甲基化在癌症中的重要性是显而易见的。然而，癌症的发生和进展仍然难以捉摸。明确证明特定基因的基因突变会导致疾病。在人类肺癌中，p16 启动子迫切需要“靶向”方法来推进表观遗传学领域的发展。甲基化相关的表观遗传沉默是最早检测到的表观突变之一，被认为发挥作用作为肿瘤发生中的关键起始事件，这种表观突变的重要性进一步被强调。与不同基因突变模式、癌症预后和治疗反应的关联。连接异常 DNA 甲基化、表观遗传沉默和肿瘤发生的分子途径仍然很薄弱在这方面，我们发表了第一个小鼠模型，证明了靶向 p16 表观突变。重要的是，我们的初步研究表明 p16 表突变。基于这些，与致癌 K-RAS 激活协同作用，驱动肺癌进展。发现，该提案响应 PAR-20-131：增强哺乳动物适用性的研究项目我们的总体目标是建立更忠实的人肺小鼠模型。癌症的发展并利用这种表观遗传工程小鼠模型来测试新的表观遗传具体来说，我们将： 1 - 在小鼠中采用表观遗传工程来模拟先进的模型。我们建议建立临床相关且具有免疫活性的小鼠模型。确定的遗传和表观遗传改变可驱动良性肺肿瘤向最终恶性生长 2 - 在携带驱动 p16 表观突变的小鼠肺部肿瘤中测试组合表观遗传疗法。我们建议测试表观遗传靶向药物和/或抗PD-L1免疫疗法是否可以有效在从非恶性病变到关键转变点期间抑制 p16 表突变肺肿瘤的生长这些研究将阐明表观突变在体内肺肿瘤发生中的功能作用。拟议研究的成功完成将为完善正在进行的表观遗传学提供机械原理疗法，有可能提高肺癌的生存率。