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年导致所有癌症死亡的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，LKB1肿瘤抑制基因的体细胞突变被添加到这个列表中。在肺腺癌小鼠模型中，在Kras突变激活的背景下，LKB1缺失导致肿瘤潜伏期缩短，组织学谱扩大，并倾向于转移。我们观察到缺氧诱导因子（HIF）家族成员HIF2在LKB1缺失时上调，并且在LKB1缺失的肺癌细胞系中，HIF2的敲低导致凋亡标志物的诱导，这表明HIF2介导了LKB1缺失肺癌的存活。我们假设HIF2是LKB1丢失的关键下游介质，并提出：1)在人类肺肿瘤的大型数据集中确定HIF2激活是否与LKB1突变相关。2)在体外确定LKB1丢失诱导的表型是否依赖于HIF2。3)确定体内LKB1缺失诱导的表型是否依赖于HIF2。

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.