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，导致的死亡人数超过乳腺癌、前列腺癌、结肠癌和胰腺癌的总和。肺癌的五年生存率只有15%，这说明需要新的治疗方法。视网膜母细胞瘤（Rb）功能在>70%的肺癌中丧失，Rb家族成员p130的丧失预示着不良结局。由于不存在恢复Rb家族功能的方法，因此在具有Rb家族缺陷上皮的肺上进行全局基因表达分析以鉴定具有潜在治疗效用的体内分子靶标。本文的数据鉴定Pim-1激酶为在肺癌细胞中表达的新型可药用Rb家族靶标。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促进肺癌进展的假设。提出了三个具体目标来直接检验这一假设：1）确定Pim-1抑制对体外肺癌细胞生长的后果，2）确定Pim-1表达的p130抑制的潜在机制，以及3）阐明Pim-1表达在人肺癌标本中的预后意义并确定Pim-1抑制的体内功效。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控制肺癌进展的潜在机制。我们独特的人类肺癌储存库用于确定Pim-1功能，并确定Pim-1作为肺癌患者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.