Novel Strategy for Lung Cancer Treatment using IGFBP-3

使用 IGFBP-3 治疗肺癌的新策略

• 批准号: 7060360
• 负责人: HO-YOUNG LEE
• 金额: $ 24.18万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7060360
• 关键词: antineoplastics; apoptosis; binding proteins; biological signal transduction; clinical research; confocal scanning microscopy; genetically modified animals; human tissue; immunocytochemistry; insulinlike growth factor; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplasm /cancer therapy; nonsmall cell lung cancer; phosphorylation; protein localization; serine threonine protein kinase; western blottings

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the major cause of cancer mortality in both women and men with a dismal <15% 5-year survival rate. Clearly, there is an urgent need for novel strategies to treat this disease. One strategy is to use the natural IGF binding protein, IGFBP-3, which regulates the insulin-like growth factor (IGF) pathway that plays a critical role in cell proliferation, antiapoptosis, survival, and neoplastic transformation. This proposal was based on preliminary data which have shown that: A) IGF pathway is selectively activated in NSCLC cells; B) targeting the IGF pathway selectively blocks the growth of NSCLC cells; C) IGFBP-3 has a dual role as a targeted therapeutic strategy for lung cancer treatment because it mediates IGF-independent intracellular antiproliferative and pro-apoptotic effects in addition to its IGF-dependent growth-regulatory function. The two separate pathways of IGFBP-3 may cooperate in an additive or synergistic manner to exert enhanced anti-tumor effects relative to each pathway alone; D) frequent loss of IGFBP-3 expression observed in samples from patients with stage I NSCLC were strongly associated with poor prognosis of stage I NSCLC One potential concern about the use of IGFBP-3 in lung cancer therapy is the presence of an activated protein kinase B (Akt) because we found that Akt induces the phosphorylation of IGFBP-3 leading to its degradation. Akt can be activated in NSCLC cells by IGF as well as by ras mutations and/or overexpression of members of EGFR family and their ligands, such as transforming growth factor alpha (TGF-alpha), which have been observed in 30-80% NSCLC patients. Because Akt can be activated via the Ras pathway even in cells treated with IGFBP-3 that blocks the IGF-mediated Akt activation, we hypothesize that agents, which inhibit IGF-independent Akt activity could enhance the antiproliferative effects of IGFBP-3 in NSCLC cells. Indeed, pharmacologic approach that inhibit Ras activation augmented IGFBP-3 protein level by increasing its stability and enhanced the growth inhibitory effects of IGFBP-3. This suggests that Akt plays a critical role in the function of cellular IGFBP-3 as an IGF-independent growth modulator in NSCLC cells. These and other studies have led to the following hypotheses: 1) IGFBP-3 inhibits lung cancer cell growth by virtue of its ability to bind to IGFs in addition to its IGF-independent effects. 2) Akt may inactivate IGF-independent growth-inhibitory function of IGFBP-3 by decreasing its stability due to phosphorylation in NSCLC cells. 3) Strategies to inhibit Akt activity in addition to suppressing IGF signaling will enhance the therapeutic effects of IGFBP-3 in lung cancer. In this revised RO1 application, I propose to test these hypotheses by exploring the following Specific Aims: 1) To determine whether the incidence and growth of lung tumors are inhibited by an increase in IGFBP-3 level and enhanced by loss of IGFBP-3 through the use of IGF-I transgenic mice and IGFBP-3 null mice. 2) To investigate a) whether inhibition of Akt activity will sensitize NSCLC cells to IGF-independent antiproliferative effects of IGFBP-3, and b) the mechanism through which the activation of Akt leads to NSCLC cell resistance to IGF- independent IGFBP-3 actions. 3) To explore the lung cancer therapeutic activity of a combined gene therapy approach using bicistronic adenoviral vector that inhibits the Akt activity and increases IGFBP-3 expression in IGF-I transgenic mice. We expect that the understanding the mechanism by which IGFBP-3 mediates signals for apoptosis and the mechanism that attenuates the antiproliferative effects of IGFBP-3 in NSCLC cells may lead to the development of more effective approaches to the treatment of lung cancer using IGFBP-3.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是男性和男性的癌症死亡率的主要原因，<15％的5年生存率。显然，迫切需要新的策略来治疗这种疾病。一种策略是使用天然的IGF结合蛋白IGFBP-3，该蛋白调节了胰岛素样生长因子（IGF）途径，该途径在细胞增殖，抗凋亡，存活和肿瘤转化中起着至关重要的作用。该建议基于初步数据，这些数据表明：a）在NSCLC细胞中选择性激活IGF途径； b）靶向IGF途径有选择地阻断NSCLC细胞的生长； c）IGFBP-3具有双重作用，是肺癌治疗的靶向治疗策略，因为它介导了非依赖IGF依赖性生长调控功能，介导了非依赖于IGF的细胞内抗促和促凋亡作用。 IGFBP-3的两个单独途径可能以添加或协同的方式配合，以相对于单独的每种途径发挥增强的抗肿瘤效应。 D) frequent loss of IGFBP-3 expression observed in samples from patients with stage I NSCLC were strongly associated with poor prognosis of stage I NSCLC One potential concern about the use of IGFBP-3 in lung cancer therapy is the presence of an activated protein kinase B (Akt) because we found that Akt induces the phosphorylation of IGFBP-3 leading to its degradation.可以通过IGF以及RAS突变和/或EGFR家族及其配体成员的过表达在NSCLC细胞中激活AKT，例如在30-80％NSCLC患者中观察到的EGFR家族及其配体的成员（例如转化生长因子alpha（TGF-Alpha））。因为即使在用IGFBP-3处理的细胞中，也可以通过RAS途径激活AKT，从而阻止IGF介导的AKT激活，因此我们假设抑制IGF独立AKT活性的试剂可以增强NSCLC细胞中IGFBP-3的抗抗抗抗抗抗素效应。确实，抑制RAS活化的药理方法通过提高其稳定性并增强了IGFBP-3的生长抑制作用，从而增强了IGFBP-3蛋白水平。这表明AKT在NSCLC细胞中作为IGFBP-3作为IGF非依赖性生长调节剂的功能中起着至关重要的作用。这些研究和其他研究导致了以下假设：1）IGFBP-3由于其与IGF无关的作用外的与IGF结合的能力而抑制了肺癌细胞的生长。 2）AKT可以通过降低NSCLC细胞磷酸化引起的稳定性来使IGFBP-3的非依赖性抑制生长抑制功能失活。 3）除抑制IGF信号传导外，抑制AKT活性的策略将增强IGFBP-3在肺癌中的治疗作用。在此修订后的RO1应用中，我建议通过探索以下具体目的来检验这些假设：1）确定肺肿瘤的发生和生长是否因IGFBP-3水平的增加而抑制了肺肿瘤的发病率和生长，并通过使用IGFBP-3的损失而增强了IGF-I Transgenic小鼠和IGFBP-3 Null Mice。 2）研究a）AKT活性的抑制是否会使NSCLC细胞对IGFBP-3的IGF独立抗增殖作用敏感，b）AKT激活导致NSCLC细胞对IGF-独立IGFBP-3独立IGFBP-3动作的抗性的机制。 3）探索使用双科腺病毒载体抑制AKT活性并增加IGF-I转基因小鼠中IGFBP-3表达的肺癌治疗方法的肺癌治疗活性。我们预计，IGFBP-3介导信号的凋亡以及减弱IGFBP-3在NSCLC细胞中抗磷酸化作用的机制的理解机制可能会导致使用IGFBP-3来开发更有效的方法来治疗肺癌。