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(PQ1) Progression of the airway field of injury to Kras mutant lung cancer

(PQ1) Kras 突变肺癌气道损伤的进展

基本信息

批准号：
9355580
负责人：
Humam Kadara
金额：
$ 34.69万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-21 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9355580
关键词：
Address Adenocarcinoma Cell Bioinformatics Carcinogen exposure Carcinogens Cells Characteristics Chemoprevention Clinical Data Development Disease Early treatment Event Evolution Exhibits Experimental Designs Experimental Models Exposure to G-Protein-Coupled Receptors Gene Expression Genes Genetic Goals Histology Human In Vitro Injury Knock-out Knowledge Lesion Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Maps Modeling Molecular Molecular Profiling Mus Mutation Normal Cell Nucleotides Oncogenes Oncogenic Organ Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Premalignant Premalignant Cell Prevention strategy Process Property Retinoids Risk Role Sampling Signal Transduction Smoker Smoking Study models Suggestion Surveys Tail Testing Therapeutic Agents Time Tobacco Tobacco use Tobacco-Associated Carcinogen United States Variant Veins Work airway epithelium antitumor effect cancer subtypes differential expression drug candidate drug discovery exome sequencing experimental analysis in vivo lung development mouse model mutant novel outcome forecast prevent statistics targeted agent targeted treatment therapeutic candidate transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY There are more than 90 million smokers in the United States who are at elevated risk for lung adenocarcinoma (LUAD), the most common lung cancer subtype. LUADs in smokers frequently (more than 25%) exhibit mutations in the Kras oncogene. Relative to other LUADs found in smokers, Kras mutant LUAD displays dismal prognosis. Attempts to pharmacologically target Kras have, for the most part, failed, warranting the need for new strategies for prevention and early treatment of this fatal disease. Despite this urgency, we have a poor understanding of events that drive development of Kras mutant LUAD in smokers and that would constitute targets for early treatment. Previous work revealed that visually normal smoking exposed airways carry alterations that are characteristic of adjacent LUADs, an effect referred to as “airway field of injury”. While this field is enriched with malignant properties, we do not know which field changes are induced or progress in normal or premalignant cells to give rise to Kras mutant LUAD and, if so, how we can impede this process. Our goal is to address this gap in knowledge, first determining molecular alterations in the progression of the normal-appearing airway field of injury to a Kras mutant LUAD phenotype, and second identifying agents that target these field alterations and prevent development of the malignancy. In our preliminary data, we found that mice with knockout of G-protein coupled receptor 5A (Gprc5a-/-), a retinoid-regulated gene that is prominently suppressed in human LUADs compared to normal lung, not only developed, in contrast to wild type littermates, premalignant lesions (PMLs) and LUADs after tobacco carcinogen exposure but also that these lesions harbored somatic Kras mutations, the same variants thought to act as drivers of human LUAD in smokers. We then studied the effects of tobacco carcinogen on gene expression in normal airways of Gprc5a-/- mice in order to understand early events in Kras mutant LUAD pathogenesis. Using RNA-sequencing, we found activation of oncogenic pathways in tobacco carcinogen exposed normal airways when compared to non-exposed cells at baseline, suggestive of an airway field of injury induced prior to onset of Kras mutant LUAD. We will use the tobacco carcinogen exposed Gprc5a-/- mouse as a model to study and target progression of the airway field of injury to Kras mutant LUAD. In Aim 1, we will survey, by exome sequencing, mutations that characterize the evolution of smoking exposed airway cells to Kras mutant PMLs and LUADs. In Aim 2, we will determine evolutionarily conserved airway expression profiles that progress with time following onset of smoking and signify the development of Kras mutant PMLs and LUADs. In Aim 3, we will harness the field signatures and use computational drug discovery approaches to identify agents that prevent the development of Kras mutant PMLs and inhibit progression of PMLs to LUADs. At the conclusion of our studies, we will have started to understand the evolution of Kras mutant LUAD, pointed to chemoprevention approaches for this fatal disease and contributed novel models for studying LUAD pathogenesis and tumor promoting field effects.

项目概要美国有超过 9000 万吸烟者患肺腺癌的风险较高 (LUAD)，最常见的肺癌亚型。吸烟者经常（超过 25%）表现出 LUAD Kras 癌基因突变。相对于吸烟者中发现的其他 LUAD，Kras 突变体 LUAD 显示预后不佳。药物靶向 Kras 的尝试大部分都失败了，因此需要需要新的策略来预防和早期治疗这种致命疾病。尽管情况紧急，我们还是对推动吸烟者发生 Kras 突变 LUAD 的事件知之甚少，这将成为早期治疗的目标。先前的研究表明，视觉上正常的吸烟会暴露呼吸道携带邻近 LUAD 特征的改变，这种效应被称为“气道损伤场”。尽管这个领域充满了恶性特性，我们不知道哪些领域的变化被引发或进展正常或癌前细胞产生 Kras 突变体 LUAD，如果是这样，我们如何阻止这一过程。我们的目标是解决这一知识差距，首先确定分子进展过程中的改变 Kras 突变体 LUAD 表型损伤的正常气道场，以及第二个鉴定药物针对这些领域的改变并预防恶性肿瘤的发展。在我们的初步数据中，我们发现敲除 G 蛋白偶联受体 5A (Gprc5a-/-) 的小鼠，Gprc5a-/- 是一种视黄醇调节基因，显着影响与正常肺相比，人类 LUAD 的抑制，不仅与野生型同窝小鼠相比，暴露于烟草致癌物后的癌前病变 (PML) 和 LUAD，而且这些病变携带体细胞 Kras 突变，这些突变被认为是吸烟者人类 LUAD 的驱动因素。我们然后研究了烟草致癌物对Gprc5a-/-小鼠正常气道基因表达的影响了解 Kras 突变体 LUAD 发病机制的早期事件。使用RNA测序，我们发现激活与未暴露的细胞相比，暴露于正常气道的烟草致癌物质的致癌途径基线，提示在 Kras 突变 LUAD 发作之前诱导气道损伤。我们将使用烟草致癌物暴露 Gprc5a-/- 小鼠作为模型来研究和靶向烟草气道领域的进展 Kras 突变体 LUAD 受伤。在目标 1 中，我们将通过外显子组测序调查表征吸烟的进化使气道细胞暴露于 Kras 突变 PML 和 LUAD。在目标 2 中，我们将确定进化上保守的气道表达谱在吸烟后随着时间的推移而进展标志着 Kras 突变 PML 和 LUAD 的发展。在目标 3 中，我们将利用字段签名并使用计算药物发现方法来识别阻止 Kras 突变体发展的药物 PML 并抑制 PML 进展为 LUAD。在我们的研究结束时，我们将开始了解 Kras 突变体 LUAD 的进化，指出这种致命疾病的化学预防方法并为研究 LUAD 发病机制和肿瘤促进场效应贡献了新模型。