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

描述（由申请人提供）：肺癌仍然是男性和女性癌症相关死亡的主要原因，估计在2008年占所有癌症死亡的28%。肺癌的分子分析已经确定了少量的遗传病变，如癌基因的激活和肿瘤抑制基因的失活，这似乎是其发展和维持的关键。最近，LKB 1肿瘤抑制基因的体细胞突变已被添加到该列表中。在肺腺癌小鼠模型中，突变Kras激活背景下的LKB 1缺失导致肿瘤潜伏期缩短、组织学谱扩大和转移倾向。我们已经观察到，低氧诱导因子（HIF）家族成员HIF 2在LKB 1缺失时上调，并且在LKB 1缺陷型肺癌细胞系中，HIF 2的敲低导致诱导凋亡标志物，表明HIF 2介导LKB 1缺陷型肺癌的存活。我们假设HIF 2是LKB 1丢失的关键下游介质，并提出：1）确定HIF 2激活是否与人肺肿瘤大数据集中的LKB 1突变相关。2)确定LKB 1缺失诱导的表型是否依赖于体外HIF 2。3)确定LKB 1缺失诱导的表型是否依赖于体内HIF 2。 公共卫生相关性：我们将研究HIF 2在LKB 1缺陷型肺肿瘤发生中的作用。HIF 2已被证明是肾细胞癌（RCC）中的一个真正的致癌基因，HIF 2信号传导的下游介质是对RCC患者产生积极影响的相关治疗靶点。将HIF 2定义为LKB 1缺陷型肿瘤的关键致癌介质不仅将定义LKB 1丢失背景下重要的失调信号通路，还将为在LKB 1缺陷型肺肿瘤中使用HIF抑制剂提供强有力的临床前依据。

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.