Defining the contributions by macrophages in BRAFV600E induced lung tumorigenesis

定义巨噬细胞在 BRAFV600E 诱导的肺肿瘤发生中的贡献

• 批准号: 9259950
• 负责人: Daphne R Pringle
• 金额: $ 5.09万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259950
• 关键词: Address; Advanced Malignant Neoplasm; BRAF gene; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Clinic; Clinical; Data; Development; Disease; Disease Resistance; Drug resistance; Evolution; Genetic; Genetically Engineered Mouse; Goals; Investigation; Lead; Ligands; Lung; Lung Neoplasms; MAP Kinase Gene; MEKs; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncoproteins; Pathway interactions; Patients; Pharmacology; Phosphotransferases; Play; Proteins; Proto-Oncogene Proteins B-raf; Ras/Raf; Recurrence; Research; Resistance; Role; Signal Transduction; Source; TP53 gene; Testing; Therapeutic; Time; Tumor stage; Veins; Work; beta catenin; c-myc Genes; cancer initiation; cancer pharmacology; cancer type; clinically relevant; combat; combinatorial; defined contribution; drug development; experimental study; falls; gain of function; improved; in vivo; inhibitor/antagonist; lung tumorigenesis; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; novel therapeutics; public health relevance; response; success; survival prediction; targeted agent; targeted treatment; therapeutic target; therapy development; translational cancer research; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Lung cancer is the deadliest cancer in the world and 2-3% of non-small cell lung cancers (NSCLC) are caused by mutations in the BRAF kinase. These activating BRAFV600E mutations are found in many cancer types and have been the target of much investigation. Many BRAFV600E inhibitors have been developed, including vemurafenib and dabrafenib, however, their success has been limited due to either lack of initial response (even in BRAFV600E positive cancers) or the emergence of drug-resistant disease. While efforts to target the BRAFV600E oncoprotein directly have had mixed results, another line of investigation has emerged. It has become apparent that tumor cells may be supported by the surrounding tumor microenvironment, providing a new source of tumor promoting cells and signals to be targeted for therapy. One of the main component of the microenvironment are the tumor associated macrophages (TAMs), and these cells have been shown to promote tumorigenesis in multiple cancer types. The presence of tumor infiltrating TAMs is a negative predicator of survival in NSCLC patients, suggesting these cells also play a role in lung cancer. While correlative data suggests a role for TAMs in NSCLC, no mechanisms by which they promote lung tumorigenesis has yet been identified. This project uses sophisticated genetically engineered mouse models of BRAFV600E induced lung tumorigenesis to probe the role of TAMs in NSCLC. Aim 1 focuses on the role of TAMs in promoting BRAFV600E induced lung tumor initiation. Using pharmacologic depletion of macrophages, I will determine if TAMs are required for BRAFV600E tumor initiation. Recent work from the sponsor's lab has demonstrated that BRAFV600E induced lung tumors require an intact WNT/ß-catenin/c-MYC signaling axis to form. Thus, a sub aim of aim 1 seeks to determine if TAMs are the source of these WNT ligands. This will be achieved using another mouse model which harbors a constitutively active ß-catenin protein in addition to expression of BRAFV600E. Results from aim 1 will delineate both: (1) the necessity of TAMs in BRAFV600E induced lung tumor formation and (2) if TAMs are the source of WNT ligands necessary for BRAFV600E tumor initiation. While aim 1 focuses on tumor initiation, aim 2 focuses on the more clinically important question of TAMs requirement for tumor maintenance and/or progression. The first sub aim of aim 2 will test, whether macrophage depletion in established BRAFV600E induced lung tumors can lead to tumor stasis and/or regression. The second sub aim of aim 2 seeks to determine if macrophage depletion can synergize with BRAF inhibition to lead to increased tumor regression compared to BRAF inhibition alone. Together the questions addressed in aim 2 have the potential to lead to the development of macrophage depletion as therapy for NSCLC patients. Together the experiments proposed here have the potential to elucidate molecular mechanisms by which TAMs support NSCLC and directly impact the development of therapies for patients with few other therapeutic options currently available.

 描述(申请人提供)：肺癌是世界上最致命的癌症，2-3%的非小细胞肺癌(NSCLC)是由BRAF激酶突变引起的。这些激活的BRAFV600E突变在许多癌症类型中被发现，并已成为许多研究的目标。已经开发了许多BRAFV600E抑制剂，包括维莫拉非尼和达普拉非尼，然而，由于缺乏初始反应(即使在BRAFV600E阳性癌症中也是如此)或出现耐药疾病，它们的成功一直受到限制。虽然直接针对BRAFV600E癌蛋白的努力结果喜忧参半，但另一条调查路线已经出现。很明显，肿瘤细胞可能受到周围肿瘤微环境的支持，为肿瘤的治疗提供了新的促癌细胞和信号来源。微环境的主要成分之一是肿瘤相关巨噬细胞(TAMs)，这些细胞已被证明在多种癌症类型中促进肿瘤的发生。肿瘤浸润性TAMs的存在是NSCLC患者生存的负面预测因素，这表明这些细胞在肺癌中也起到了作用。虽然相关数据表明TAMs在非小细胞肺癌中发挥了作用，但它们促进肺肿瘤发生的机制尚未确定。该项目使用BRAFV600E诱导的肺肿瘤形成的复杂基因工程小鼠模型来探索TAMS在非小细胞肺癌中的作用。目的1研究TAMS在促进BRAFV600E诱导的小鼠肺肿瘤形成中的作用。通过对巨噬细胞的药理学去除，我将确定BRAFV600E肿瘤启动是否需要TAMS。赞助商实验室最近的工作表明，BRAFV600E诱导的肺肿瘤需要一个完整的WNT/？-catenin/c-myc信号轴才能形成。因此，目标1的一个子目标试图确定TAMS是否是这些WNT配体的来源。这将使用另一种小鼠模型来实现，该模型除了表达BRAFV600E外，还含有具有结构性活性的ç-catenin蛋白。AIM 1的结果将描述：(1)TAMS在BRAFV600E诱导的肺肿瘤形成中的必要性；(2)TAMS是否是BRAFV600E肿瘤形成所需的WNT配体的来源。虽然目标1专注于肿瘤的启动，而目标2专注于更重要的临床问题，即肿瘤维持和/或进展所需的TAMS。目标2的第一个子目标将测试，在已建立的BRAFV600E诱导的肺肿瘤中，巨噬细胞耗尽是否会导致肿瘤停滞和/或消退。目标2的第二个子目标试图确定与单独抑制BRAF相比，巨噬细胞耗竭是否可以与抑制BRAF协同导致肿瘤消退。总之，目标2中提出的问题有可能导致巨噬细胞耗竭作为非小细胞肺癌患者治疗的发展。总之，这里提出的实验有可能阐明TAMs支持非小细胞肺癌的分子机制，并直接影响目前几乎没有其他治疗选择的患者的治疗方法的发展。