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

描述(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年所有癌症死亡中有28%是由肺癌引起的。对肺癌的分子分析已经确定了少量的遗传损伤，如癌基因的激活和肿瘤抑制基因的失活，这些似乎对肺癌的发展和维持至关重要。最近，LKB1抑癌基因的体细胞突变也被添加到这个列表中。在肺腺癌的小鼠模型中，在突变的Kras激活的背景下，LKB1的缺失导致了较短的肿瘤潜伏期，扩大了组织学谱，并有转移的倾向。我们观察到，低氧诱导因子(HIF)家族成员HIF2在LKB1缺失后上调，在LKB1缺失的肺癌细胞系中，HIF2的下调导致了凋亡标志物的诱导，提示HIF2介导了LKB1缺失的肺癌的生存。我们假设HIF2是LKB1缺失的关键下游调节因子，并建议：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)确定LKB1缺失诱导的表型是否依赖于HIF2。3)在体内确定LKB1缺失诱导的表型是否依赖于HIF2。 公共卫生相关性：我们将研究HIF2在LKB1缺陷肺肿瘤发生中的作用。HIF2已被证明是肾细胞癌(RCC)中一个真正的癌基因，HIF2信号的下游介导物是相关的治疗靶点，对RCC患者产生了积极的影响。将HIF2定义为LKB1缺陷性肿瘤的关键致癌介质，不仅将在LKB1缺失的背景下定义一个重要的失控信号通路，而且还将为HIF抑制剂在LKB1缺陷性肺肿瘤中的应用提供强有力的临床前理论依据。

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.