Novel Strategy for Lung Cancer Treatment using IGFBP-3

使用 IGFBP-3 治疗肺癌的新策略

• 批准号: 6885417
• 负责人: HO-YOUNG LEE
• 金额: $ 24.76万
• 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/6885417
• 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)是导致女性和男性癌症死亡的主要原因，5年生存率低达15%。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，它调节胰岛素样生长因子(IGF)途径，该途径在细胞增殖、抗凋亡、生存和肿瘤转化中发挥关键作用。这一建议基于以下初步数据：A)IGF通路在NSCLC细胞中被选择性地激活；B)靶向IGF通路选择性地阻断NSCLC细胞的生长；C)IGFBP-3作为肺癌治疗的靶向治疗策略具有双重作用，因为它除了具有IGF依赖的生长调节功能外，还介导IGF非依赖性的细胞内抗增殖和促凋亡作用。相对于每条通路，IGFBP-3的两条独立通路可能以相加或协同方式发挥更强的抗肿瘤效果；d)在I期NSCLC患者样本中经常观察到IGFBP-3表达的缺失，这与I期NSCLC不良预后密切相关；d)IGFBP-3用于肺癌治疗的一个潜在的担忧是激活的蛋白激酶B(Akt)的存在，因为我们发现Akt诱导IGFBP-3的磷酸化导致其降解。在NSCLC细胞中，AKT可以被IGF激活，也可以通过ras突变和/或EGFR家族成员及其配体的过度表达而激活，如转化生长因子α(TGF-α)，已在30-80%的NSCLC患者中观察到。由于即使在经IGFBP-3阻断IGF介导的Akt激活的细胞中，Akt也可以通过RAS途径被激活，我们推测，抑制IGF非依赖性Akt活性的药物可以增强IGFBP-3在NSCLC细胞中的抗增殖作用。事实上，抑制RAS激活的药理学方法通过增加IGFBP-3的稳定性来增加IGFBP-3的蛋白水平，并增强IGFBP-3的生长抑制作用。这表明Akt在非小细胞肺癌细胞中作为IGF非依赖性生长调节剂在细胞IGFBP-3的功能中起着关键作用。这些研究和其他研究得出了以下假设：1)IGFBP-3通过与IGF结合的能力抑制肺癌细胞的生长，此外，IGFBP-3还具有IGF非依赖性作用。2)Akt可能通过磷酸化降低IGFBP-3在NSCLC细胞中的稳定性，从而使IGFBP-3的生长抑制功能失活。3)除抑制IGF信号外，抑制Akt活性的策略将增强IGFBP-3对肺癌的治疗效果。在这个修订的RO1应用中，我建议通过探索以下具体目标来检验这些假设：1)通过使用IGF-I转基因小鼠和IGFBP-3缺失小鼠，确定IGFBP-3水平的增加是否抑制了肺癌的发生和生长，而IGFBP-3的缺失是否促进了肺癌的发生和生长。2)研究抑制Akt活性是否会使NSCLC细胞对IGFBP-3的IGF非依赖性抗增殖作用敏感，以及b)Akt激活导致NSCLC细胞对IGF非依赖性IGFBP-3作用产生抵抗的机制。3)探讨双顺反子腺病毒载体联合基因治疗IGF-I转基因小鼠肺癌的作用。我们期望，了解IGFBP-3介导细胞凋亡信号的机制以及减弱IGFBP-3在非小细胞肺癌细胞中的抗增殖作用的机制可能会导致开发更有效的使用IGFBP-3治疗肺癌的方法。