p130 and Pim-1 as prognostic biomarkers and therapeutic targets in lung cancer

描述（由申请人提供）：肺癌是全球癌症死亡的主要原因，其死亡人数超过乳腺癌、前列腺癌、结肠癌和胰腺癌的总和。肺癌的5年生存率只有15%，强调需要新的治疗方法。视网膜母细胞瘤（Rb）功能在70%的肺癌中丧失，Rb家族成员p130的丧失预示着预后不佳。由于没有恢复Rb家族功能的方法，我们对Rb家族缺乏上皮的肺进行了全局基因表达分析，以确定具有潜在治疗效用的体内分子靶点。本文的数据表明Pim-1激酶是在肺癌细胞中表达的一种新的可药物Rb家族靶点。本研究的目的是验证Rb/p130联合缺失通过增强Pim-1介导的肿瘤细胞存活来促进肺癌进展的假设。为了直接验证这一假设，我们提出了三个具体目标：1)在体外确定Pim-1抑制对肺癌细胞生长的影响；2)确定p130抑制Pim-1表达的机制；3)阐明Pim-1在人肺癌标本中的表达对预后的意义，并确定Pim-1在体内的抑制效果。拟议的研究将确定Pim-1抑制对肺癌细胞生长的影响，并确定Pim-1和Rb/p130控制肺癌进展的机制。我们独特的人类肺癌库用于确定Pim-1的功能，并确定Pim-1作为肺癌患者的新型靶向治疗的预后和治疗潜力。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death worldwide leading to more deaths than breast, prostate, colon and pancreatic cancers combined. Lung cancer has a dismal 15% five year survival rate emphasizing need for novel therapy. Retinoblastoma (Rb) function is lost in >70% of lung cancers and loss of the Rb family member p130 portends a poor outcome. Since no methods exist to restore Rb family function, global gene expression analysis was performed on lungs with Rb family deficient epithelium to identify in vivo molecular targets with potential therapeutic utility. Data herein identify Pim-1 kinase as a novel druggable Rb family target expressed in lung cancer cells. The goal of this proposal is to test the hypothesis that combined Rb/p130 loss promotes lung cancer progression by enhancing Pim-1 mediated tumor cell survival. Three specific aims are proposed to directly test this hypothesis: 1) Determine the consequence of Pim-1 inhibition on lung cancer cell growth in vitro, 2) determine mechanisms underlying p130 suppression of Pim-1 expression, and 3) elucidate the prognostic significance of Pim-1 expression in human lung cancer specimens and determine efficacy of Pim-1 inhibition in vivo. Proposed studies will determine the effects of Pim-1 inhibition on lung cancer cell growth and define mechanisms underlying Pim-1 and Rb/p130 control of lung cancer progression. Our unique human lung cancer repository is used to determine Pim-1 function and define the prognostic and therapeutic potential of Pim-1 as a novel targeted therapy for lung cancer patients.