The molecular and immune evolution in the progression of lung neoplasia to invasive adenocarcinoma

肺肿瘤进展为侵袭性腺癌的分子和免疫进化

• 批准号: 10328878
• 负责人: Jianjun Zhang
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328878
• 关键词: Address; Adenocarcinoma; Adenocarcinoma In Situ; Animal Model; Atypical adenomatous hyperplasia; Bioinformatics; Biological Markers; Cancer Gene Mutation; Cancer Model; Clinical; Clinical Trials; Collection; Complex; Data; Detection; Development; Diagnostic Imaging; Disease Progression; Dose; Epidermal Growth Factor Receptor; Event; Evolution; Genetically Engineered Mouse; Genomics; Heterogeneity; High Resolution Computed Tomography; Human; Immune; Immunologic Surveillance; Immunology; Immunoprevention; Immunosuppression; Immunotherapy; Incidence; KRAS2 gene; Lesion; Lung; Lung Adenocarcinoma; Lung nodule; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular; Molecular Evolution; Mus; Neoplasms; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; PD-1 blockade; PD-1/PD-L1; PD-L1 blockade; Pathology; Patients; Prevention; Preventive; Productivity; Randomized; Recording of previous events; Research; Resected; Risk; STK11 gene; Sampling; Specimen; Spiral Computed Tomography; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Time; Translational Research; Work; anti-PD-1; base; carcinogenesis; cohort; genomic biomarker; high risk; immune checkpoint blockade; immunotherapy trials; insight; lung cancer prevention; lung carcinogenesis; lung development; minimally invasive; molecular marker; mouse model; mutant; neoplastic; novel; pembrolizumab; personalized diagnostics; phase II trial; preservation; prevent; screening; standard of care; tumor; tumor progression

Project summary/abstract Little is known about the molecular mechanisms underlying early carcinogenesis of lung adenocarcinoma (ADC), the most common subtype of lung cancer. Atypical adenomatous hyperplasia (AAH) is the only recognized preneoplasia. AAH is postulated to progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and eventually invasive ADC. However, the molecular landscape of these lesions has not yet been well characterized and the definition and management of these lesions remain controversial. Our preliminary data have demonstrated a progressive increase in genomic complexity and immunosuppression with neoplastic progression from AAH, to AIS, MIA, and invasive ADC indicating continuous genomic evolution and “immunoediting”. This work led to our recently approved immunoprevention trial, “IMPRINT-Lung: Randomized phase II trial of immunotherapy for the prevention of non-small cell lung cancers using pembrolizumab”. We herein hypothesize: 1) Immune escape contributes to progression of lung preneoplasia; 2) Higher levels of molecular complexity are associated with less effective cancer immunosurveillance; and 3) Immune checkpoint blockade at pre- and early neoplastic stages prevents or delays the development of invasive ADC. We will investigate our hypotheses in the following aims. In Aim 1, we will utilize a large, unique cohort of resected AAH, AIS, MIA and invasive ADC to define and compare the molecular and immune profiles to identify molecular and immune features that characterize specific lung preneoplasia stages and subsequent progression. Next, in Aim 2, we will leverage the valuable specimens from the IMPRINT-Lung trial to a) determine molecular and immune features associated with progression or regression of high-risk IPNs and identify biomarkers to select patients suitable for observation versus immunoprevention; b) discover novel targets and strategies for lung cancer prevention. Finally in Aim 3, we will develop and characterize human- relevant lung ADC preneoplasia murine models by a) defing the molecular and immune landscapes of lung preneoplasia in EGFR-mutant, KRAS/TP53-mutant and KRAS/LKB1-mutant genetically engineered murine models (GEMMs); b) determining whether PD1/PDL1 blockade prevents invasive lung ADC in GEMMs; and c) test potential novel targets for lung cancer prevention using lung preneoplasia GEMMs based on insights gained from Aims 1 and 2. I have a proven track record of productivity in defining the molecular heterogeneity and evolution of early stage lung adenocarcinomas and have assembled a team with expertise in genomics, bioinformatics, immunology, translational research, genetically engineered mouse models, and pathology to tackle these specific aims.

项目摘要/摘要 关于肺腺癌的早期致癌作用的分子机制知之甚少 （ADC），最常见的肺癌亚型。非典型腺瘤增生（AAH）是唯一的 公认的肿瘤。 AAH被张贴到原位（AIS）的腺癌进展中，微创 腺癌（MIA），最终是侵入性ADC。但是，这些病变的分子景观具有 尚未得到很好的特征，这些病变的定义和管理仍然存在争议。我们的 初步数据表明基因组复杂性和免疫抑制的逐渐增加 从AAH到AIS，MIA和侵入性ADC的肿瘤进展，表明连续基因组进化 和“免疫程序”。这项工作导致了我们最近批准的免疫预防审判“烙印： 免疫疗法的随机II期试验，用于预防非小细胞肺癌 pembrolizumab”。我们在这里假设：1）免疫逃生有助于肺部肿瘤的发展； 2）较高水平的分子复杂性与效果较低的癌症免疫监视有关； 3） 免疫检查点在前和早期肿瘤阶段进行阻止，以防止或延迟发展 入侵ADC。我们将在以下目标中调查我们的假设。在AIM 1中，我们将利用大型，独特的 切除的AAH，AIS，MIA和侵入性ADC的队列，以定义和比较分子和免疫特征 识别特征特定肺前鼻阶段的分子和免疫特征，随后 进展。接下来，在AIM 2中，我们将利用烙印肺试验中的宝贵标本 a）确定与高危IPN的进展或回归相关的分子和免疫特征 并确定生物标志物以选择适合观察与免疫预防的患者； b）发现小说 预防肺癌的目标和策略。最终，在AIM 3中，我们将发展并描述人类 - a）捍卫肺的分子和免疫景观 EGFR突变，KRAS/TP53突变和KRAS/LKB1突变的基因工程鼠 模型（宝石）; b）确定PD1/PDL1阻断是否阻止了GEMMS中的浸润性肺ADC；和c） 测试潜在的新型肺癌预防靶标，该目标是基于洞察力的肺前疟原虫宝石 从目标1和2中获得。在定义分子异质性方面，我有一个可靠的生产力记录 以及早期肺腺癌的发展，并组建了一个具有基因组学专业知识的团队， 生物信息学，免疫学，翻译研究，基因工程的小鼠模型和病理学 解决这些特定目标。