Intercepting progression from pre-invasive to invasive lung adenocarcinoma

阻止从浸润前肺腺癌向浸润性肺腺癌的进展

• 批准号: 10117907
• 负责人: NASSER Khaled ALTORKI
• 金额: $ 13.06万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117907
• 关键词: Adenocarcinoma; Adenocarcinoma In Situ; Agreement; Antibodies; Archives; Biology; Case Series; Catalogs; Cells; Chemoprevention; Clinical; Collection; Custom; Data; Detection; Development; Diagnostic radiologic examination; Disease; Disease Progression; Disease-Free Survival; Event; Fluorescence Microscopy; Foundations; Frequencies; Fresh Tissue; Future; Gene Expression Profiling; Histologic; Histology; Human; Image; Immune; Immune Targeting; Immunofluorescence Immunologic; Indolent; Intercept; Investigation; Lesion; Longitudinal Studies; Lung; Lung Adenocarcinoma; Lung nodule; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Metastatic Neoplasm to Lymph Nodes; Methods; Molecular; Molecular Profiling; Mutation; Natural History; Nodule; Non-Small-Cell Lung Carcinoma; Pathology; Pathway interactions; Patients; Phase; Phenotype; Prevention; Resected; Resolution; Rest; Role; Sampling; Severities; Smoker; Testing; Therapeutic; Transcriptional Regulation; X-Ray Computed Tomography; base; cancer cell; cancer invasiveness; cancer subtypes; cell type; cohort; comparative; driver mutation; exome sequencing; experimental study; global health; high risk; imaging modality; improved; insight; lung carcinogenesis; microscopic imaging; minimally invasive; mouse model; neoplastic cell; never smoker; novel; pre-clinical; preclinical study; prevent; protein expression; single cell analysis; transcriptome sequencing; treatment strategy; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

Abstract Despite advances in therapeutic strategies, non-small cell lung cancer remains a deadly disease. An improved understanding of the biology of lung cancer is needed to intercept the disease at an early point in its progression. Our project, which is inspired by that challenge, focuses on events transpiring in the earliest radiographically-detected manifestation of lung cancer: the computerized tomography (CT)-detected non- solid nodule, of which as many as 40% harbor frankly invasive adenocarcinoma. Thus, despite conventional wisdom that CT-detected non-solid nodules represent pre or minimally invasive malignancy, clearly transition to more invasive histologies occurs in a significant proportion of these nodules. Understanding the cellular and molecular changes within non-solid nodules that drive progression will provide unique and novel insights into the fundamental mechanisms of lung carcinogenesis. We hypothesize that alterations in cells of the tumor microenvironment (TME) have a role in initiating and supporting this progression. In agreement with that proposal, our preliminary multiplex immunofluorescence (IF) studies suggest that progression to a more invasive phenotype is associated with the development of a strong immunosuppressive TME. In this project we test our hypothesis using multidimensional methods to profile the TME and to determine the crosstalk between cancer cells and the TME in pre-invasive to invasive human lung non-solid adenocarcinomas. Comparative analysis of the cellular and molecular events associated with the distinct histological stages will lead to identification of the critical events triggering progression and thereby identify targets to intercept disease progression. We will use appropriate mouse models in pre-clinical studies to develop these targets as strategies to intercept progression of pre-invasive to invasive cancer. In the first phase of these studies (UG3 phase), we will define TME alterations associated with progression of lung nodules using RNAseq profiling and image-based methods (multiplex IF and imaging CyTOF) in studies of our archival tumor samples. These studies will generate a comprehensive catalogue of the cellular and molecular events that trigger progression of indolent lesions to frankly invasive cancers, with a strong focus on immune mechanisms. These analyses will provide novel and detailed insights into how the composition and activity of the TME changes with progression. In the second phase (UH3 phase), we will leverage mouse models to explore interception strategies to target immune mechanisms and prevent progression. The proposed cohort satisfies the RFA’s focus on High-Risk Cohorts for Cancer-Immunoprevention Studies, since lung nodules are premalignancies highly prevalent in smokers.

摘要 尽管治疗策略取得了进展，但非小细胞肺癌仍然是一种致命的疾病。一个 需要更好地了解肺癌的生物学，以便在早期阶段拦截这种疾病。 它的进程。我们的项目是受这一挑战的启发，专注于最早发生的事件 肺癌的X线表现：CT未检出 实性结节，其中多达40%的结节有明显的浸润性腺癌。因此，尽管常规 明智的是，CT检测到的非实性结节代表着早期或微创的恶性肿瘤，明显的过渡 更具侵袭性的组织学改变发生在这些结节中的很大一部分。 了解推动进展的非固体结节内的细胞和分子变化将提供 对肺癌发生的基本机制的独特和新颖的见解。我们假设 肿瘤微环境(TME)细胞的改变在启动和支持这一过程中起着作用 进步。与这一建议一致，我们的初步多重免疫荧光(IF)研究 提示进展为更具侵袭性的表型与强直性 免疫抑制药TME。在这个项目中，我们使用多维方法来测试我们的假设 TME和测定肿瘤细胞与TME之间的串扰 肺非实性腺癌。与细胞和分子事件相关的比较分析 不同的组织学阶段将导致识别触发进展的关键事件和 从而确定阻止疾病进展的目标。我们将在临床前使用合适的小鼠模型 研究开发这些靶点作为拦截侵袭前期到浸润性癌症进展的策略。 在这些研究的第一阶段(UG3阶段)，我们将定义与进展相关的TME改变 在研究中使用RNAseq分析和基于图像的方法(多重IF和成像细胞TOF)的肺结节 我们的肿瘤样本档案。这些研究将产生一个全面的细胞和 引发惰性病变进展为直接浸润性癌症的分子事件，具有强烈的焦点 关于免疫机制的。这些分析将提供新的和详细的洞察如何构成 TME活性随病程进展而变化。在第二阶段(UH3阶段)，我们将利用鼠标 探索针对免疫机制和防止进展的拦截策略的模型。 建议的队列满足了RFA对癌症免疫预防研究高危队列的关注， 由于肺结节是常见的恶性肿瘤，在吸烟者中非常常见。