Lung Adenocarcinoma: From Genome Alterations to Therapeutic Discovery

肺腺癌：从基因组改变到治疗发现

• 批准号: 10683176
• 负责人: MATTHEW L. MEYERSON
• 金额: $ 102.37万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683176
• 关键词: American; Aneuploidy; BRAF gene; Cancer Etiology; Cancer Patient; Categories; Cell Proliferation; Cessation of life; Chromosomal Rearrangement; Clinical; DNA; Deaminase; Dependence; Diagnosis; Disease; Engineering; Epidermal Growth Factor Receptor; Epitopes; Gene Amplification; Gene Dosage; Gene Mutation; Genes; Genetic Enhancer Element; Genome; Genome engineering; Genomic approach; Genomics; Goals; Human; Immune Targeting; Immunologics; Immunotherapy; Individual; Interferons; Knowledge; Laboratories; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Modification; Mutate; Mutation; Nucleic Acid Cleavage; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Persons; Prevention; RNA; Research; T-Lymphocyte; Therapeutic; Tumor Suppressor Genes; United States; Work; cancer cell; cancer genome; cell growth; effective therapy; falls; functional genomics; gene function; genome-wide; improved; insight; mortality; new therapeutic target; novel; novel strategies; targeted treatment; tool

Project Summary The introduction of new targeted therapies and immunotherapies has led to significant decreases in lung cancer mortality in the United States in recent years. However, lung cancer continues to kill over 135,000 Americans each year, and over a million people annually world-wide. Thus, there remains 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. The focus of my laboratory is to understand somatic genome alterations in human lung cancer, to use this understanding to elucidate lung cancer pathogenesis, and in turn to improve diagnosis and treatment. We have been honored to participate in many clinically impactful genomic discoveries, including the discoveries of BRAF and EGFR mutations that guide targeted therapy use. In recent work, we continue to advance knowledge of lung cancer genomes and their function. We described novel oncogenic mutations in lung cancer, the duplication of super-enhancer elements near known oncogenes. We analyzed the cancer-causing activity of lung adenocarcinoma mutated genes such as SOS1 and MGA; we initiated genomic approaches to immunological targets such as the ADAR RNA deaminase gene; and we generated a genomically engineered model of aneuploidy for lung cancer. 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 described in 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 shown here 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 knowledge gained from the proposed research will deepen our understanding of human lung adenocarcinoma and will drive novel and effective treatments for lung cancer patients.

项目摘要 新的靶向治疗和免疫治疗的引入导致肺癌的显着下降 美国近年来的死亡率。然而，肺癌继续杀死超过135，000美国人 全世界每年有超过一百万人。因此，仍然迫切需要继续 改善对这一致命疾病的预防、诊断和治疗。 我们的研究重点是肺腺癌，最常见的肺癌形式。肺 腺癌从根本上说是一种基因组疾病。我的实验室的重点是了解体细胞 人类肺癌中的基因组改变，利用这种理解来阐明肺癌的发病机制， 从而改善诊断和治疗。我们很荣幸能够参与许多具有临床影响力的 基因组发现，包括指导靶向治疗使用的BRAF和EGFR突变的发现。 在最近的工作中，我们继续推进肺癌基因组及其功能的知识。我们 描述了肺癌中新的致癌突变， 已知的癌基因我们分析了肺腺癌突变基因的致癌活性， 我们启动了针对免疫学靶点（如阿达尔RNA）的基因组方法 脱氨酶基因;并且我们产生了肺癌的非整倍体的基因组工程模型。 我们提出的研究福尔斯分为三大类： 1.单基因改变：我们将分析突变和拷贝数改变的机制。 改变是肺腺癌发病机制的基础。本建议书所述的例子包括 肿瘤抑制基因CMTR 2和谱系癌基因NKX 2 -1，其是最显著扩增的 基因在肺腺癌中的表达。 2.免疫学靶点鉴定：我们将使用基因组方法来表征免疫学靶点。 肺癌的特征和潜在的脆弱性。这里展示的例子包括对基因的持续研究 参与干扰素途径中的RNA传感和修饰，也是癌症依赖性，以及 大规模功能基因组筛选以鉴定作为肺癌中T细胞的抗原性靶标的表位。 3.全基因组特征。我们继续研究非整倍体和基因剂量效应对 细胞生长和增殖。此外，我们正在开发一种新的基于基因组的治疗方法： 针对肺癌DNA中“新基因组”的酸裂解疗法。这种方法将利用小说 通过使用基因组工程工具由癌症中的染色体重排产生的基因组序列 专门针对癌细胞。 我的目标是，从拟议的研究中获得的知识将加深我们对 人类肺腺癌，并将推动肺癌患者的新的和有效的治疗。

项目成果

Illuminating the noncoding genome in cancer.

• DOI: 10.1038/s43018-020-00114-3
• 发表时间: 2020-09
• 期刊: NATURE CANCER
• 影响因子: 22.7
• 作者: Zhang, Xiaoyang;Meyerson, Matthew
• 通讯作者: Meyerson, Matthew

Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069.

• DOI: 10.1021/acs.jmedchem.2c01379
• 发表时间: 2022-11-10
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Orsi, Douglas L.;Pook, Elisabeth;Braeuer, Nico;Friberg, Anders;Lienau, Philip;Lemke, Christopher T.;Stellfeld, Timo;Bruggemeier, Ulf;Putter, Vera;Meyer, Hanna;Baco, Maria;Tang, Stephanie;Cherniack, Andrew D.;Westlake, Lindsay;Bender, Samantha A.;Kocak, Mustafa;Strathdee, Craig A.;Meyerson, Matthew;Eis, Knut;Goldstein, Jonathan T.
• 通讯作者: Goldstein, Jonathan T.

Insertions and Deletions Target Lineage-Defining Genes in Human Cancers.

插入和缺失针对人类癌症中的谱系定义基因。

• DOI: 10.1016/j.cell.2016.12.025
• 发表时间: 2017-01-26
• 期刊: Cell
• 影响因子: 64.5
• 作者: Imielinski M;Guo G;Meyerson M
• 通讯作者: Meyerson M

Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists.

作为共价 PPARG 反向激动剂的口服生物可利用的 4-氯-6-氟间苯二甲酰胺的发现和表征。

• DOI: 10.1016/j.bmc.2022.117130
• 发表时间: 2023
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Orsi,DouglasL;Ferrara,StevenJ;Siegel,Stephan;Friberg,Anders;Bouché,Léa;Pook,Elisabeth;Lienau,Philip;Bluck,JosephP;Lemke,ChristopherT;Akcay,Gizem;Stellfeld,Timo;Meyer,Hanna;Pütter,Vera;Holton,SimonJ;Korr,Daniel;Jerchel-Fu
• 通讯作者: Jerchel-Fu

MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma.

• DOI: 10.1158/0008-5472.can-16-1944
• 发表时间: 2017-08-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Lu X;Peled N;Greer J;Wu W;Choi P;Berger AH;Wong S;Jen KY;Seo Y;Hann B;Brooks A;Meyerson M;Collisson EA
• 通讯作者: Collisson EA