Elucidating Mechanisms of Lung Tumor Regression

阐明肺肿瘤消退的机制

• 批准号: 7114321
• 负责人: WILLIAM PAO
• 金额: $ 13.62万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7114321
• 关键词: apoptosis; athymic mouse; biological signal transduction; disease /disorder model; embryonic stem cell; enzyme activity; fibroblasts; gene mutation; genetic transcription; immunocytochemistry; laboratory mouse; lung neoplasms; mitogen activated protein kinase; molecular oncology; neoplasm /cancer genetics; neoplasm /cancer remission /regression; oncogenes; phosphatidylinositol 3 kinase; protein structure function; survivin; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): This revised proposal details a 4-year training program for the development of an academic career in cancer biology. Having recently completed clinical training in medical oncology, the Principal Investigator (PI) will use this dedicated period to acquire the knowledge and skills necessary to become an independent researcher. The PI will be mentored by a leading cancer biologist, Dr. Harold Varmus, who has trained numerous productive scientists. The Memorial Sloan-Kettering Cancer Center will provide institutional support. Ample resources and multiple career development activities will be available to help the PI achieve his goals. Research will focus on lung cancer, the leading cause of cancer-related mortality worldwide. The lab has developed a mouse model of lung cancer which shows that the continued expression of activated K-ras is required for the maintenance of lung tumors. This suggests that tumor cell death could be induced by targeting molecules that regulate this process. The studies proposed are designed to elucidate the mechanisms of lung tumor regression. The hypothesis is that lung tumor cells expressing the K-ras oncogene have undergone adaptive changes in gene transcription and/or protein expression such that they require the continued presence of activated K-ras for viability. Preliminary data suggest that major Ras signaling pathways and/or inhibitor of apoptosis proteins (lAPs) are probably involved. To study this further, we will use 2 experimental approaches: the lung cancer mice, and a more flexible model system that the PI has developed in which transformed murine embryonic fibroblasts (MEFs) also display dependence on activated K-ras for tumor survival. Although MEF and lung tumors are derived from different cell types, the MEF tumor regression model phenocopies that seen in the lung, suggesting that shared mechanisms may exist. Findings obtained from studies of MEF tumor regression will be verified in lung tumors. Specific aims include 1) determining if/which major Ras signaling pathways mediate activated K-ras-dependent tumor maintenance, and 2) assessing the impact of lAPs in maintaining tumor survival. The long-range goal is to identify molecular targets to induce apoptosis in human lung cancers.

描述（由申请人提供）：该修订后的提案详细介绍了一个为期 4 年的癌症生物学学术职业发展培训计划。首席研究员 (PI) 最近完成了医学肿瘤学的临床培训，将利用这段专门时间来获取成为独立研究员所需的知识和技能。 PI 将接受一位领先的癌症生物学家 Harold Varmus 博士的指导，他培养了许多多产的科学家。纪念斯隆-凯特琳癌症中心将提供机构支持。我们将提供充足的资源和多种职业发展活动来帮助 PI 实现其目标。 研究将集中于肺癌，这是全世界癌症相关死亡的主要原因。该实验室开发了一种肺癌小鼠模型，该模型表明激活的 K-ras 的持续表达是维持肺肿瘤所必需的。这表明肿瘤细胞死亡可以通过调节这一过程的靶向分子来诱导。所提出的研究旨在阐明肺肿瘤消退的机制。假设是表达 K-ras 癌基因的肺肿瘤细胞在基因转录和/或蛋白质表达方面经历了适应性变化，因此它们需要持续存在激活的 K-ras 才能维持活力。初步数据表明，主要的 Ras 信号通路和/或凋亡蛋白抑制剂 (lAP) 可能参与其中。为了进一步研究这一点，我们将使用两种实验方法：肺癌小鼠，以及 PI 开发的更灵活的模型系统，其中转化的小鼠胚胎成纤维细胞 (MEF) 也表现出对激活的 K-ras 肿瘤存活的依赖。尽管 MEF 和肺肿瘤源自不同的细胞类型，但 MEF 肿瘤回归模型在肺中观察到表型，表明可能存在共同的机制。 MEF 肿瘤消退研究的结果将在肺部肿瘤中得到验证。具体目标包括 1) 确定是否/哪些主要 Ras 信号通路介导激活的 K-ras 依赖性肿瘤维持，以及 2) 评估 lAP 在维持肿瘤存活方面的影响。长期目标是确定诱导人类肺癌细胞凋亡的分子靶标。