Novel Strategy for Lung Cancer Treatment using IGFBP-3

使用 IGFBP-3 治疗肺癌的新策略

• 批准号: 7245130
• 负责人: HO-YOUNG LEE
• 金额: $ 23.48万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7245130
• 关键词: Accounting; Ad5CMV; Address; Adenovirus Vector; Adenoviruses; Aerosols; Affinity; Animal Model; Apoptosis; Apoptotic; Attenuated; Binding; Biological Availability; Caliber; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Cell Proliferation; Cell Survival; Cell physiology; Cells; Combined Modality Therapy; Data; Development; Diagnosis; Disease; Dominant-Negative Mutation; Epidemiologic Studies; Epithelial Cells; Family; Farnesyl Transferase Inhibitor; Goals; Growth; Half-Life; Human; In Vitro; Incidence; Induction of Apoptosis; Infection; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor-Binding Proteins; Knockout Mice; Lead; Ligands; Lung; Lung Adenoma; Lung Neoplasms; MEKs; Malignant neoplasm of lung; Maps; Measures; Mediating; Microscopy; Modeling; Mus; Mutagenesis; Mutation; Neoplastic Cell Transformation; Non-Small-Cell Lung Carcinoma; Numbers; Partner in relationship; Pathway interactions; Patients; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-akt; Recombinants; Relative (related person); Resistance; Risk; Role; SCH 66336; Sampling; Serum; Signal Pathway; Signal Transduction; Somatomedins; Specificity; Staging; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Time; Transforming Growth Factor alpha; Transgenic Mice; Treatment Efficacy; Treatment Protocols; Tumor Weights; Validation; Woman; aerosolized; analog; base; cancer cell; cancer therapy; cytotoxicity; extracellular; gallium alloy GF; gene therapy; human IGFBP2 protein; improved; in vivo; inhibitor/antagonist; member; men; mortality; mutant; novel strategies; outcome forecast; receptor; research study; size; therapeutic target; tumor; tumor progression

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（申请人提供）：非小细胞肺癌（NSCLC）是女性和男性癌症死亡的主要原因，5年生存率<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，其调节在细胞增殖、抗凋亡、存活和肿瘤转化中起关键作用的胰岛素样生长因子（IGF）途径。该建议基于初步数据，这些数据表明：A）IGF途径在NSCLC细胞中选择性活化; B）靶向IGF途径选择性阻断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，因为除了其IGF依赖性生长调节功能外，IGFBP-3还介导IGF非依赖性细胞内抗增殖和促凋亡作用。IGFBP-3的两个独立途径可能以相加或协同的方式合作，相对于每个单独的途径发挥增强的抗肿瘤作用; D）在I期NSCLC患者的样品中观察到的IGFBP-3表达的频繁缺失与I期NSCLC的不良预后密切相关。Akt），因为我们发现Akt诱导IGFBP-3的磷酸化，导致其降解。Akt可在NSCLC细胞中被IGF以及ras突变和/或EGFR家族成员及其配体（如转化生长因子α（TGF-α））的过表达激活，这已在30-80%的NSCLC患者中观察到。因为Akt可以通过Ras途径激活，即使在用IGFBP-3处理的细胞中，IGFBP-3阻断IGF介导的Akt激活，我们假设抑制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活化的药理学方法通过增加IGFBP-3的稳定性来增加IGFBP-3蛋白水平，并增强IGFBP-3的生长抑制作用。这表明Akt在NSCLC细胞中作为IGF非依赖性生长调节剂的细胞IGFBP-3的功能中起关键作用。这些和其他研究导致了以下假设：1）IGFBP-3除了其IGF非依赖性作用之外，还通过其结合IGF的能力来抑制肺癌细胞生长。2)Akt可能通过降低IGFBP-3在NSCLC细胞中的磷酸化稳定性来抑制IGFBP-3的IGF非依赖性生长抑制功能。3)除了抑制IGF信号传导之外，抑制Akt活性的策略将增强IGFBP-3在肺癌中的治疗效果。在本修订的RO 1申请中，我提议通过探索以下具体目的来检验这些假设：1）通过使用IGF-I转基因小鼠和IGFBP-3缺失小鼠，确定肺肿瘤的发病率和生长是否受到IGFBP-3水平升高的抑制以及IGFBP-3缺失的增强。2)研究a）Akt活性抑制是否会使NSCLC细胞对IGFBP-3的IGF非依赖性抗增殖作用敏感，和B）Akt激活导致NSCLC细胞对IGF非依赖性IGFBP-3作用耐药的机制。3)目的探讨双顺反子腺病毒介导的抑制Akt活性和提高IGFBP-3表达的联合基因治疗IGF-I转基因小鼠肺癌的作用。我们希望了解IGFBP-3介导细胞凋亡信号的机制和减弱IGFBP-3在NSCLC细胞中的抗增殖作用的机制，可能会导致开发使用IGFBP-3治疗肺癌的更有效方法。