Evaluate the antiangiogenic properties of mda-7/IL-24

描述(申请人提供)：肺癌是全球最主要的死亡原因。据估计，美国每年将诊断出17.5万例新的肺癌病例，占死亡人数的15.7万人以上。尽管肺癌的治疗策略取得了进展，但总体存活率不到6个月。这是由于无法控制肿瘤的局部扩散，以及未能治疗已转移到远处的肿瘤。因此，迫切需要开发一种治疗方法，不仅能抑制原发肿瘤的生长，还能抑制转移到远处的肿瘤。因此，新形式的治疗模式是必要的。一种新的治疗方法是利用一种既能作为靶向肿瘤的抗肿瘤药物，又能抑制肿瘤血管生成的药物。因此，既能控制原发肿瘤又能控制远处转移的基因可以成为治疗癌症的有效药物。其中一个新发现的分子是黑色素瘤分化相关基因-7(MDA-7)，也被称为白介素24(IL-24)。MDA-7基因对一系列癌细胞的抗肿瘤活性在体外和体内都得到了很好的证明。初步研究表明，MDA-7/IL-24蛋白可分泌(sMDA-7/IL-24)，并抑制与体外血管生成相关的内皮细胞或毛细血管“管状”结构。基于这些初步观察，我们推测sMDA-7/IL-24具有抗血管生成活性。为了进一步验证我们的假设，拟议的研究将集中于以下四个具体目标： 目的：研究sMDA-7/IL-24对血管内皮细胞的体外抗血管生成作用。 目的：探讨sMDA-7/IL-24的抗血管生成作用是否与受体有关。 目的：探讨sMDA-7/IL-24抑制血管生成的机制。 目的：评价sMDA-7/IL-24在肿瘤模型中的体内效应。该方案中设计的实验将使用分子和细胞模型来评估抗血管生成活性。 本方案中设计的实验将证明sMDA-7/IL-24具有强大的抗血管生成活性，并将为进一步开发MDA-7作为一种抗癌治疗药物奠定基础，最终将导致其转化为临床。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of death worldwide. Each year an estimated 175,000 new cases of lung cancer will be diagnosed, accounting for over 157,000 deaths annually in the USA. Despite advances in the treatment strategies for lung cancer the overall survival rate is less than 6-months. This is due to the inability to control local spread of the tumor as well as failure to treat tumors that have metastasized to distant sites. Thus, there is an urgent need for developing a therapeutic that not only inhibits primary tumor growth but also tumors that have metastasized to distant sites. Therefore, novel forms of treatment modalities are mandated. One such novel therapeutic approach is the utilization of an agent that functions both, as an antitumor agent targeting the tumor and as an anti-angiogenic agent directed at inhibiting tumor vascularization. Thus a gene that can control both, primary tumor and tumor metastatic at a distant site can be an effective therapeutic agent for cancer treatment. One such newly identified molecule is the melanoma differentiation associated gene-7 (mda-7) also known as interleukin-24 (IL-24). The antitumor activity of mda-7 gene against a spectrum of cancer cells is well documented both, in vitro and in vivo. Preliminary studies indicate that the MDA-7/IL-24 protein is secreted (sMDA-7/IL-24) and inhibited endothelial cell or capillary "tube"-Iike structures, an in vitro correlate of angiogenesis. Based on these preliminary observations we hypothesize that sMDA-7/IL-24 possess anti-angiogenic activity. To further test our hypothesis the proposed studies will focus on the following four specific aims: Aim 1: Investigate the anti-angiogenic activity of sMDA-7/IL-24 on endothelial cells in vitro. Aim 2: Investigate whether the anti-angiogenic activity of sMDA-7/IL-24 is receptor mediated. Aim 3: Evaluate the mechanism by which sMDA-7/IL-24 inhibits angiogenesis. Aim 4: Evaluate the in vivo efficacy of sMDA-7/IL-24 in tumor model studies. The experiments designed in this proposal will use molecular and cellular models to assess the antiangiogenic activity. The experiments designed in this proposal will demonstrate that sMDA-7/IL-24 has potent anti-angiogenic activity and will provide the foundation for further development of mda-7 as an anticancer therapeutic that will ultimately result in translation to the clinic.