NKX2-1 Enhancer Amplification and Lineage Addiction in Lung Adenocarcinoma

项目摘要 每年有超过13.5万美国人死于肺癌，每年有100多万人死于肺癌 世界范围内。因此，迫切需要继续提高预防、诊断和治疗水平。 治疗这种致命疾病。我们的研究重点是肺腺癌，最 常见的肺癌。肺腺癌从根本上说是一种基因组疾病。我们的 建议的研究分为三大类：1.单基因改变：我们将分析 突变和拷贝数改变的机制构成了 肺腺癌的发病机制。这项提案的例子包括肿瘤 抑癌基因CMTR2和谱系癌基因NKX2-1是最显著的 肺腺癌中的扩增基因。2.免疫靶标识别：我们将使用 用基因组学方法研究肺癌的免疫学特征及其潜在意义 漏洞。例如，对参与RNA传感的基因的持续研究。 干扰素途径的修饰也是癌症依赖的，以及大规模的 筛选肺内T细胞抗原表位的功能基因组筛选 癌症。3.全基因组特征。我们继续研究非整倍体和基因的功能 剂量对细胞生长和增殖的影响。此外，我们正在开发一种新的方法 以基因组为基础的治疗：针对肺中“新基因组”的核酸切割疗法 癌症DNA。这种方法将利用新的基因组序列，其结果是 利用基因组工程工具特异性靶向治疗癌症中的染色体重排 癌细胞。我的目标是，拟议中的研究将加深我们对人类的理解 并将推动肺癌患者的新的、有效的治疗方法。 目的1：肺腺癌基因水平变化的功能研究 1A.CMTR2抑癌基因的功能分析。 2A。为什么NKX2-1在肺腺癌中扩增？ 目的2：确定肺腺癌免疫靶点的全基因组方法 2A。RNA修饰途径：从ADAR到XRN1 2B。肺癌中突变表位特异性T细胞受体的鉴定 目的3：肺腺癌基因组水平的改变 3A.评估基因剂量在染色体丢失影响中的作用 3B.以肺癌新基因组为靶点的核酸治疗

Project Summary Lung cancer kills over 135,000 Americans each year, and over a million people annually world-wide. Thus, there is an urgent need to continue to improve the prevention, diagnosis and treatment of this deadly disease. Our research focuses on lung adenocarcinoma, the most common form of lung cancer. Lung adenocarcinoma is, at its root, a disease of the genome. Our proposed research falls into three broad categories: 1. Single gene alterations: we will analyze the mechanisms by which both mutations and copy number alterations underlie the pathogenesis of lung adenocarcinoma. Examples from this proposal include the tumor suppressor gene CMTR2 and the lineage oncogene NKX2-1, which is the most significantly amplified gene in lung adenocarcinoma. 2. Immunological target identification: we will use genomic approaches to characterize immunological features of lung cancer and potential vulnerabilities. Examples include continued studies of genes involved in RNA sensing & modification in the interferon pathway that are also cancer dependencies, as well as large-scale functional genomic screens to identify epitopes that are antigenic targets of T cells in lung cancer. 3. Genome-wide features. We continue to study aneuploidy and the function of gene dosage effects on cell growth and proliferation. In addition, we are developing a new approach for genome-based therapy: nucleic acid cleavage therapies that target the “neo-genome” in lung cancer DNA. This approach would exploit the novel genomic sequences that result from chromosomal rearrangements in cancer by using genome engineering tools to specifically target cancer cells. My goal is that the proposed research will deepen our understanding of human lung adenocarcinoma and will drive novel, effective treatments for lung cancer patients. Aim 1: Functional studies of gene level alterations in lung adenocarcinoma 1a. Functional analysis of the CMTR2 tumor suppressor gene. 2a. Why is NKX2-1 amplified in lung adenocarcinoma? Aim 2: Genome-wide approaches to identifying immunological targets in lung adenocarcinoma 2a. RNA modification pathways: from ADAR to XRN1 2b. Identifying T cell receptors specific for mutated epitopes in lung cancer Aim 3: Genome-level alterations in lung adenocarcinoma 3a. Assessing the role of gene dosage in the impact of chromosome loss 3b. Targeting the lung cancer neo-genome with nucleic acid therapy