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: 10465296
• 负责人: NASSER Khaled ALTORKI
• 金额: $ 84.53万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10465296
• 关键词: Intercepting; progression; pre; invasive; lung

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.

抽象的 尽管治疗策略取得了进步，非小细胞肺癌仍然是一种致命的疾病。 需要加深对肺癌生物学的了解，以便及早阻止这种疾病的发生。 我们的项目受到这一挑战的启发，重点关注最早发生的事件。 肺癌的放射学检测表现：计算机断层扫描 (CT) 检测到的非 实性结节，其中多达 40% 含有明显的侵袭性腺癌。 CT 检测到的非实性结节代表前期或微创恶性肿瘤，明显过渡 这些结节中很大一部分出现了更具侵袭性的组织学特征。 了解非实性结节内驱动进展的细胞和分子变化将提供 对肺癌发生的基本机制有独特而新颖的见解。 肿瘤微环境（TME）细胞的改变在启动和支持这一过程中发挥着作用 与该提议一致，我们的初步多重免疫荧光 (IF) 研究正在进行中。 表明向更具侵袭性的表型的进展与强大的 在这个项目中，我们使用多维方法来检验我们的假设，以分析免疫抑制 TME。 TME 并确定侵入前至侵入性人类中癌细胞与 TME 之间的串扰 肺非实体腺癌相关细胞和分子事件的比较分析。 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靶标。因此，我们将在临床前使用适当的小鼠模型。 研究开发这些目标作为拦截浸润前癌症进展的策略。 在这些研究的第一阶段（UG3 阶段），我们将定义与疾病进展相关的 TME 改变 研究中使用 RNAseq 分析和基于图像的方法（多重 IF 和成像 CyTOF）对肺结节进行研究 我们的档案肿瘤样本的这些研究将生成一个全面的细胞和肿瘤目录。 引发惰性病变进展为明显侵袭性癌症的分子事件，重点关注 这些分析将为了解该成分如何发挥作用提供新颖而详细的见解。 在第二阶段（UH3 阶段），TME 的活性会随着进展而变化。 模型探索针对免疫机制和预防进展的拦截策略。 拟议的队列满足 RFA 对癌症免疫预防研究高风险队列的关注， 因为肺结节是吸烟者中非常常见的癌前病变。