Epigenetically Engineered Mouse Model for Lung Cancer Therapy

项目摘要(摘要) DNA甲基化异常在癌症中的重要性是显而易见的。DNA甲基化在人类免疫系统中的基础作用 然而，癌症的发生和发展仍然难以捉摸。基因打靶技术在动物模型中的应用 明确地证明了特定基因的基因突变会导致疾病。一个类似的“表观遗传基因” 为了推进表观遗传学领域的发展，迫切需要“靶向”方法。在人类肺癌中，p16启动子 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，被认为具有功能 作为肿瘤发生过程中的关键启动事件。这一评价的重要性得到了进一步强调 与不同的基因突变模式、癌症预后和治疗反应的相关性。然而， 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少 特色化的。在这方面，我们发表了第一个小鼠模型，证明了靶向p16突变 推动自发性肿瘤的发展。重要的是，我们的初步研究显示，p16突变 与致癌的K-RAS激活协同作用，推动肺癌的进展。基于这些 发现，这项建议回应PAR-20-131：增强哺乳动物适用性的研究项目 翻译研究的模型。我们的总体目标是建立更可靠的人肺小鼠模型 肿瘤的发生和利用这种表观遗传工程小鼠模型来测试新的表观遗传学 治疗策略。具体地说，我们将：1利用小鼠的表观遗传工程来模拟晚期− 人类肺癌。我们建议建立具有临床相关性和免疫活性的小鼠模型 关于明确的基因和表观遗传改变推动肺部良性肿瘤向终极恶性生长 表型。2检测携带驱动基因p16突变的小鼠肺癌的−联合表观遗传治疗。 我们建议测试表观遗传靶向药物和/或抗PD-L1免疫疗法是否有效 在从非恶性病变到非恶性病变的关键过渡点抑制p16突变的肺癌生长 腺癌。这些研究将阐明表位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提供完善正在进行的表观遗传学的机制基础 治疗，有可能提高肺癌的存活率。

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.