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 尽管在治疗策略方面取得了进步，但非小细胞肺癌仍然是一种致命的疾病。一个 需要提高对肺癌生物学的了解，以便早期拦截该疾病 它的进展。我们的项目受到挑战的启发，重点是最早的事件 肺癌射线照相发现的表现：计算机断层扫描（CT）检测的非 - 固体结节，其中多达40％的含量为富有侵入性腺癌。那是多矿的传统 CT检测到的非固体结节代表前或微创恶性肿瘤，明显过渡的智慧 对于更多的侵入性组织学，这些结节中很大一部分发生。 了解驱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。我们假设这一点 肿瘤微环境（TME）细胞的改变在启动和支持中起作用 进展。与该提案一致，我们的初步多重免疫荧光（IF）研究 表明向更具侵入性表型的发展与强大的发展有关 免疫抑制TME。在这个项目中，我们使用多维方法检验我们的假设，以概述 TME并确定癌细胞与TME之间的串扰，以侵入性人类的侵入性人 肺非稳态腺癌。对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对触发进展的关键事件的识别和 从而确定拦截疾病进展的靶标。我们将在临床前使用适当的鼠标模型 研究这些目标是拦截侵入性侵入性癌症进展的策略。 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 研究中使用RNASEQ分析和基于图像的方法（IF和Imaging Cytof）的肺结节 我们的档案肿瘤样品。这些研究将产生细胞和 分子事件会触发懒惰病变的进展到坦率地侵入性癌症，重点很强 关于免疫机制。这些分析将提供新颖和详细的见解 TME的活性随进展而变化。在第二阶段（UH3阶段），我们将利用鼠标 探索拦截策略以靶向免疫机制并防止进展的模型。 拟议的队列满足了RFA对癌症免疫预防研究的高风险队列的关注， 由于肺结是在吸烟者中极为普遍的预先作用。