Determining the Molecular Contributions of KDM2A in NSCLC Metastasis

确定 KDM2A 在 NSCLC 转移中的分子贡献

• 批准号: 10687982
• 负责人: Carolyn Kravitz
• 金额: $ 3.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687982
• 关键词: Address; Animal Model; Bioinformatics; Biological; Biological Assay; Biological Process; Blood; Brain; Cancer Biology; Cancer Patient; Cell Death; Cell Survival; Cells; Cessation of life; ChIP-seq; Chemicals; Circulation; Clinical; Clinical Research; Co-Immunoprecipitations; Comet Assay; Country; Cultured Cells; Curative Surgery; DNA Damage; DNA Repair; Data; Development; Diagnosis; Disease; Epidermal Growth Factor Receptor; Epigenetic Process; Excision; Gamma-H2AX; Genome Stability; Genotoxic Stress; Goals; Growth; Human; Hypoxia; Immunofluorescence Immunologic; Immunohistochemistry; Immunotherapy; Impairment; In Vitro; Injections; Invaded; Ionizing radiation; KRAS2 gene; KRASG12D; Knowledge; Laboratories; Ligation; LoxP-flanked allele; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Methylation; Methyltransferase; Migration Assay; Mission; Modality; Modeling; Molecular; Monitor; Mus; National Cancer Institute; Neoplasm Metastasis; Newly Diagnosed; Non-Small-Cell Lung Carcinoma; Nude Mice; Pathway interactions; Patients; Platinum; Proliferating; Proteins; Quality of life; Reactive Oxygen Species; Research; Role; Series; Site; Solid Neoplasm; Stream; Stress; Systemic Therapy; TP53 gene; Techniques; Therapeutic; Tissue Sample; Tissues; Transcriptional Regulation; Ubiquitination; United States; Work; advanced disease; cancer survival; chemotherapy; demethylation; driver mutation; expectation; functional genomics; genomic biomarker; immune cell infiltrate; improved; in vivo; in vivo Model; inhibitor; knock-down; lung cancer cell; mortality; mutant; novel; preservation; prevent; response; small hairpin RNA; standard of care; synergism; therapeutic target; therapy development; transcriptome sequencing; tumor; tumor microenvironment

PROJECT SUMMARY Non-Small Cell Lung Cancer (NSCLC) remains the highest mortality cancer in the United States, with approximately 70% of patients not eligible for curative surgical resection at diagnosis. Thus, the advent of novel systemic therapeutics, especially those which are efficacious for metastatic disease, is of primary importance. A functional genomic screen conducted in our laboratory identified the H3K36 demethylase KDM2A as a regulator of KRAS/P53 mutant NSCLC metastasis. KDM2A is known to also have roles in DNA damage repair, thus I hypothesize that KDM2A is important to preserving the genomic stability of NSCLC cells by mediating genotoxic stress, and to metastasis by controlling transcriptional responses to the tumor microenvironment. The primary aims of this project are to elucidate the molecular mechanism by which KDM2A promotes NSCLC proliferation/survival, and to determine the steps of the metastatic cascade for which KDM2A is important. To answer these questions I will leverage bioinformatic analysis, functional mutants, and animal models. In Aim 1, I will use functional mutants of KDM2A to assay importance of each functional domain to proliferation and survival, as well as assaying the impact of KDM2A loss on markers of genomic stress. In Aim 2, I will use in vivo models of metastasis to examine the molecular functions of KDM2A that are important to various steps of the metastatic cascade, as well as using a variety of injection and assay techniques to pinpoint the step(s) of the cascade at which KDM2A is important. The completion of this project will reveal the molecular mechanism of a novel potential clinical target of advanced NSCLC. My project is easily translatable to clinical research, as a research grade chemical inhibitor of KDM2A exists and could be optimized for clinical deployment.

项目总结 非小细胞肺癌(NSCLC)仍然是美国死亡率最高的癌症， 约70%的患者在确诊时不符合根治性手术切除的条件。因此，出现了 新的系统疗法，特别是那些对转移性疾病有效的疗法，是主要的。 重要性。本实验室进行的功能基因组筛选鉴定了H3K36去甲基酶 KDM2A作为KRAS/P53突变型NSCLC转移的调节因子已知KDM2a在DNA中也有作用 损伤修复，因此我假设KDM2A对于保持NSCLC细胞的基因组稳定性是重要的 通过介导基因毒性应激，并通过控制对肿瘤的转录反应来促进转移 微环境。这个项目的主要目的是阐明分子机制 KDM2A促进非小细胞肺癌增殖/存活，并确定其转移级联反应的步骤 KDM2A很重要。为了回答这些问题，我将利用生物信息学分析、功能突变和 动物模型。在目标1中，我将使用KDM2A的功能突变体来测试每个功能的重要性 结构域对增殖和生存的影响以及分析KDM2A缺失对基因组标志物的影响 压力。在目标2中，我将使用体内转移模型来研究KDM2A的分子功能，这些功能包括 重要的是转移级联的各个步骤，以及使用各种注射和检测 准确定位KDM2a在级联中起重要作用的步骤(S)的技术。这项工程的完成 将揭示晚期非小细胞肺癌新的潜在临床靶点的分子机制。我的项目是 易于转化为临床研究，作为KDM2A的研究级化学抑制剂存在，并可能 针对临床部署进行了优化。