NKX2-1 Enhancer Amplification and Lineage Addiction in Lung Adenocarcinoma

项目摘要 每年有超过135，000名美国人死于肺癌， 世界范围内。因此，迫切需要继续改进预防、诊断和 治疗这种致命的疾病。我们的研究重点是肺腺癌， 肺癌的常见形式。从根本上说，肺腺癌是一种基因组疾病。我们 拟议的研究福尔斯三大类：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。该提案的例子包括肿瘤 抑制基因CMTR 2和谱系癌基因NKX 2 -1，这是最显著的 肺腺癌中的基因扩增。2.免疫学目标识别：我们将使用 基因组学方法表征肺癌的免疫学特征和潜在的 漏洞例子包括继续研究与RNA传感有关的基因， 干扰素途径的修饰也是癌症依赖性，以及大规模的 功能性基因组筛选以鉴定作为肺中T细胞的抗原靶的表位 癌3.全基因组特征。我们继续研究非整倍体和基因的功能， 对细胞生长和增殖的剂量效应。此外，我们正在开发一种新的方法， 对于基于基因组的治疗：靶向肺部“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， 通过使用基因组工程工具， 癌细胞我的目标是，拟议的研究将加深我们对人类的理解， 肺腺癌，并将推动新的，有效的治疗肺癌患者。 目的1：肺腺癌基因水平改变的功能研究 1a. CMTR 2肿瘤抑制基因的功能分析。 2a.为什么NKX 2 -1在肺腺癌中扩增？ 目的2：全基因组方法鉴定肺腺癌的免疫靶点 2a. RNA修饰途径：从阿达尔到XRN 1 2b.肺癌突变表位特异性T细胞受体的鉴定 目的3：肺腺癌的基因组水平改变 3a.评估基因剂量在染色体丢失影响中的作用 3b.靶向肺癌新基因组的核酸治疗

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