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: 10374786
• 负责人: Carolyn Kravitz
• 金额: $ 4.27万
• 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/10374786
• 关键词: Address; Animal Model; Bioinformatics; Biological; Biological Assay; Biological Process; Blood; Blood Circulation; Brain; Cancer Biology; Cancer Patient; Cell Death; Cell Survival; Cells; Cessation of life; ChIP-seq; Chemicals; Chemotherapy and/or radiation; Clinical; Clinical Research; Co-Immunoprecipitations; Comet Assay; Country; DNA Damage; DNA Repair; Data; Development; Diagnosis; Disease; Epidermal Growth Factor Receptor; Epigenetic Process; Excision; Gamma-H2AX; Genetic Transcription; Genome Stability; Genotoxic Stress; Goals; Growth; Human; Hypoxia; Immunofluorescence Immunologic; Immunohistochemistry; Immunotherapy; Impairment; In Vitro; Injections; Ionizing radiation; KRAS2 gene; KRASG12D; Knowledge; Laboratories; Ligation; 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; Nonmetastatic; Nude Mice; Operative Surgical Procedures; Pathway interactions; Patients; Platinum; Proteins; Quality of life; Reactive Oxygen Species; Research; Role; Series; Site; Solid Neoplasm; Stream; Stress; Systemic Therapy; TP53 gene; Techniques; Therapeutic; Tissue Sample; Tissues; Tumor-infiltrating immune cells; Ubiquitination; United States; Work; advanced disease; cancer survival; demethylation; driver mutation; expectation; functional genomics; genomic biomarker; 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.

项目摘要 非小细胞肺癌（NSCLC）仍然是美国死亡率最高的癌症， 大约70%的患者在诊断时不适合进行根治性手术切除。因此， 新的全身性治疗剂，尤其是对转移性疾病有效的那些， 重要性我们实验室进行的功能基因组筛选鉴定了H3 K36脱甲基酶 KDM 2A作为KRAS/P53突变型NSCLC转移的调节剂。已知KDM 2A也在DNA中起作用 损伤修复，因此我假设KDM 2A对保持NSCLC细胞的基因组稳定性很重要 通过介导遗传毒性应激，并通过控制对肿瘤的转录反应来转移 微环境。本项目的主要目的是阐明 KDM 2A促进NSCLC增殖/存活，并确定转移级联的步骤， KDM 2A很重要。为了回答这些问题，我将利用生物信息学分析，功能突变体， 动物模型在目的1中，我将使用KDM 2A的功能突变体来分析每个功能突变体的重要性。 结构域对增殖和存活的影响，以及测定KDM 2A缺失对基因组标记物的影响。 应力在目标2中，我将使用体内转移模型来检查KDM 2A的分子功能， 重要的是转移级联的各个步骤，以及使用各种注射和测定 技术来精确定位KDM 2A重要的级联步骤。该项目的建成 将揭示晚期NSCLC的一个新的潜在临床靶点的分子机制。我的项目是 容易转化为临床研究，作为KDM 2A的研究级化学抑制剂， 优化临床部署。