MicroRNA-based interventions to prevent progression from lung preneoplasia to adenocarcinoma

基于 MicroRNA 的干预措施可预防肺肿瘤前期发展为腺癌

• 批准号: 9379210
• 负责人: Roy S Herbst
• 金额: $ 20.76万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-26 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379210
• 关键词: Address; Adenocarcinoma; Alpha Cell; Atypical adenomatous hyperplasia; Automobile Driving; Benign; Binding; Biological Assay; Biological Markers; Cancer Etiology; Cancer Patient; Cells; Characteristics; Critical Pathways; DNA Sequence Alteration; Data; Detection; Development; Diagnosis; Dimensions; Disease; Epidermal Growth Factor Receptor; Event; Formalin; Frequencies; Gene Expression; Genetic Transcription; Goals; Growth; Heterogeneity; Inflammation; Inflammation Mediators; Inflammatory; Intervention; KRAS2 gene; Laboratories; Lesion; Link; Lung; Lung Adenocarcinoma; Lung Neoplasms; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular Profiling; Mutant Strains Mice; Neoplasms; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Nuclear; Oncogenic; Organoids; Paraffin Embedding; Pathology; Pathway interactions; Patients; Play; Premalignant; Premalignant Cell; Primary Neoplasm; Research; Role; Serum; Signal Pathway; Signal Transduction; Site; Specimen; Structure; Structure of parenchyma of lung; Survival Rate; TP53 gene; Techniques; Testing; Therapeutic; Tissues; Transcript; Transgenic Mice; Tumor Initiators; Tumor Tissue; Untranslated RNA; Up-Regulation; adenoma; base; cancer stem cell; genetic profiling; improved; inhibitor/antagonist; innovation; locked nucleic acid; mortality; mouse model; nanoparticle; neoplastic cell; novel; overexpression; precursor cell; prevent; programs; response; standard of care; stemness; treatment response; tumor; tumor initiation; tumor progression; tumorigenesis

PROJECT SUMMARY This proposal titled “MicroRNA-based interventions to prevent progression from lung preneoplasia to adenocarcinoma” is responsive to PQ1. Lung cancer is the most common cause of cancer-related mortality worldwide. Despite advances in detection and improvements to standard of care, the overall survival rate for lung cancer patients remains very low (5). This poor survival rate is probably due to the relatively advanced stage of the disease at diagnosis. If lung cancer could be identified and stopped at a preneoplastic stage prior to progression into advanced stage, we could improve the patients' survival. However, little is known about the biomarkers distinguishing preneoplasia from normal tissues and the molecules driving preneoplasia initiation and progression. Recent evidence has shown that intratumor cellular heterogeneity contributes to tumor initiation and progression of cancer, including lung cancer (6). Tumor-initiating cells (TICs) or cancer stem cells are a subpopulation of the bulk of tumor cells that can recapitulate the whole tumor's heterogeneous structures and functionally drive tumorigenesis. Nuclear factor-κB (NF-κB) is the key mediators of the inflammation response and has been recently been implicated as a driver of TICs (7). More recently, it has been found that inflammation can change expression of some microRNAs (miRNAs), including upregulation of oncogenic miR-21 (8). MiRNAs are non-coding RNAs belonging to a novel class of regulatory molecules that control gene expression by binding to complementary sites on multiple target messenger RNA (mRNA) transcripts simultaneously (9). However, the signaling events that link cancer stemness-related miRNAs to preneoplasia initiation and progression in inflammatory microenvironments remain to be charted. We hypothesize that inflammation induced miRNA dysregulation on TICs might drive preneoplasia initiation and progression in KRASmut or epidermal growth factor receptor (EGFRmut) lung adenocarcinoma patients, and that a deeper understanding of this may identify novel targets for miRNA-based therapeutics. In Aim 1, we will characterize a miRNA signature in preneoplasia in lung tissues. In Aim 2, we will investigate roles of miRNA inhibitors or mimics in preventing progression from preneoplasia to neoplasia in lung. At the conclusion of these studies, we will have generated a new tumor organoid model, developed miRNA therapeutics useful in curing preneoplasia and preventing malignant progression, as well as gained innovative information regarding roles of both TICs and the inflammatory niche in preneoplasia initiation and progression.

项目概要 该提案题为“基于 MicroRNA 的干预措施，防止肺肿瘤前期发展为肺肿瘤前期”。 腺癌”对 PQ1 有反应。 尽管检测技术取得了进步，但肺癌仍是全球癌症相关死亡的最常见原因。 随着护理标准的提高，肺癌患者的总体生存率仍然很低 (5)。 这种低生存率可能是由于诊断时肺部疾病处于相对较晚的阶段。 癌症可以在进展到晚期之前的肿瘤前阶段被识别和阻止，我们 可以提高患者的生存率然而，人们对区分癌前病变的生物标志物知之甚少。 最近的证据表明，来自正常组织和驱动肿瘤前期发生和进展的分子。 研究表明，肿瘤内细胞异质性有助于肿瘤的发生和癌症的进展，包括 肺癌 (6) 肿瘤起始细胞 (TIC) 或癌症干细胞是大部分肿瘤细胞的一个亚群。 可以概括整个肿瘤的异质结构并在功能上驱动肿瘤核发生。 因子-κB (NF-κB) 是炎症反应的关键介质，最近被认为是 TIC 的驱动因素 (7) 最近发现炎症可以改变某些表达。 microRNA (miRNA)，包括致癌 miR-21 的上调 (8)。 属于一类新型调节分子，通过与互补物结合来控制基因表达 多个靶标信使 RNA (mRNA) 转录本上的位点同时存在 (9)。 将癌症干性相关的 miRNA 与炎症的肿瘤前期起始和进展联系起来 微环境仍有待绘制，我们认为炎症会导致 miRNA 失调。 TIC 可能驱动 KRASmut 或表皮生长因子受体肿瘤前期的起始和进展 （EGFRmut）肺腺癌患者，对此进行更深入的了解可能会发现新的靶标 对于基于 miRNA 的治疗，我们将描述肺肿瘤前期的 miRNA 特征。 在目标 2 中，我们将研究 miRNA 抑制剂或模拟物在预防进展中的作用。 在这些研究结束时，我们将产生一种新的肿瘤。 类器官模型，开发了可用于治疗肿瘤前期和预防恶性肿瘤的 miRNA 疗法 进展，并获得有关 TIC 和炎症生态位作用的创新信息 在肿瘤前期的起始和进展中。