Characterization and therapeutic targeting of HIF in LKB1 - deficient lung cancer

LKB1 缺陷型肺癌中 HIF 的表征和治疗靶向

基本信息

批准号：
8034821
负责人：
WILLIAM Y. KIM
金额：
$ 29.66万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8034821
关键词：
Adhesions Alleles Apoptosis Biological Markers CXCR4 gene Cancer Etiology Cancer cell line Cells Cellular Stress Cessation of life Data Data Set Development Disease Down-Regulation Embryo Extracellular Matrix Degradation FDA approved Family member Fibroblasts Gene Targeting Genes Genetic Genomics Histologic Histology Human Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway In Vitro LOX gene Lesion Ligation Lung Adenocarcinoma Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Matrix Metalloproteinases Mediating Mediator of activation protein Messenger RNA Molecular Analysis Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nutrient Oncogene Activation Oncogenes Oncogenic Pathway interactions Patients Phenotype Platelet-Derived Growth Factor Play Process Protein-Serine-Threonine Kinases Proteins Renal Cell Carcinoma Role STK11 gene Signal Pathway Signal Transduction Sirolimus Somatic Mutation Squamous Cell Squamous Differentiation Staining method Stains Stromal Cell-Derived Factor 1 Therapeutic Thrombospondin 1 Tissue Microarray Tuberous sclerosis protein complex Tumor Suppressor Genes Tumor-Suppressor Gene Inactivation Up-Regulation Variant Vascular Endothelial Growth Factors Woman cancer cell epithelial to mesenchymal transition in vivo in vivo Model inhibitor/antagonist knock-down lung Carcinoma lung tumorigenesis mTOR protein men metastatic process migration mortality mouse model mutant pre-clinical public health relevance response restoration therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Lung cancer remains the leading cause of cancer related mortality in both men and women and is estimated to cause 28% of all cancer deaths in 2008. Molecular analysis of lung carcinomas has identified a small number of genetic lesions such as activation of oncogenes and inactivation of tumor suppressor genes that appear to be critical for their development and maintenance. Recently, somatic mutations of the LKB1 tumor suppressor gene have been added to this list. In a mouse model of lung adenocarcinoma, LKB1 deletion on a backdrop of mutant Kras activation results in a shorter tumor latency, an expanded histological spectrum, and a propensity towards metastasis. We have observed that the hypoxia-inducible factor (HIF) family member, HIF2, is upregulated upon LKB1 loss and that in LKB1-deficient lung cancer cell lines knock- down of HIF2 results in the induction of markers of apoptosis, suggesting that HIF2 mediates the survival of LKB1-deficient lung cancers. We hypothesize that HIF2 is a critical downstream mediator of LKB1 loss and propose: 1) To determine whether HIF2 activation correlates with LKB1 mutation in a large dataset of human lung tumors. 2) To determine whether the phenotype induced by LKB1 loss is dependent upon HIF2 in vitro. 3) To determine whether the phenotypes induced by LKB1 loss are dependent upon HIF2 in vivo. PUBLIC HEALTH RELEVANCE: We will investigate the role of HIF2 in the tumorigenesis of LKB1-defective lung tumors. HIF2 has been shown to be a bona fide oncogene in renal cell carcinoma (RCC) and downstream mediators of HIF2 signaling are the relevant therapeutic targets that have resulted in positive impact for RCC patients. Defining HIF2 as a critical oncogenic mediator of LKB1-defective tumors will not only define an important deregulated signaling pathway in the setting of LKB1 loss but also give strong preclinical rationale to the use of HIF inhibitors in LKB1- defective lung tumors.

描述（由申请人提供）：肺癌仍然是男性和女性癌症相关死亡率的主要原因，据估计在2008年造成所有癌症死亡的28％。肺癌的分子分析已经确定了少量的遗传病变。随着癌基因的激活和肿瘤抑制基因的灭活，似乎对它们的发育和维持至关重要。最近，LKB1肿瘤抑制基因的体细胞突变已添加到此列表中。在肺腺癌的小鼠模型中，突变体Kras激活背景下的LKB1缺失导致肿瘤潜伏期较短，组织学谱扩大和转移倾向。我们已经观察到，缺氧诱导因子（HIF）家族成员HIF2在LKB1丢失后上调，并且在LKB1缺陷型肺癌细胞系中，HIF2敲低HIF2导致凋亡的诱导，这表明HIF2介导了HIF2介导LKB1缺陷型肺癌的生存。我们假设HIF2是LKB1损失的关键下游介体，并提出：1）确定HIF2激活是否与大型人肺肿瘤数据集中的LKB1突变相关。 2）确定LKB1损失引起的表型是否取决于体外HIF2。 3）确定LKB1损失诱导的表型是否取决于体内HIF2。公共卫生相关性：我们将研究HIF2在LKB1缺陷肺肿瘤的肿瘤发生中的作用。 HIF2已被证明是肾细胞癌（RCC）中的真正癌基因，而HIF2信号传导的下游介质是相关的治疗靶标，对RCC患者产生了积极影响。将HIF2定义为LKB1缺陷肿瘤的关键致癌介质不仅会在LKB1损失的情况下定义重要的放松信号传导途径，而且还为在LKB1缺陷型肺肿瘤中使用HIF抑制剂提供了强烈的临床前理由。