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

描述（由申请人提供）：肺癌是全球主要的死亡原因。每年估计有175，000例新的肺癌病例将被诊断出来，在美国每年有超过157，000例死亡。尽管肺癌的治疗策略取得了进展，但总体生存率不到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剂，其不仅抑制原发性肿瘤生长，而且抑制已转移到远处部位的肿瘤。因此，新形式的治疗模式是强制性的。一种这样的新的治疗方法是利用既作为靶向肿瘤的抗肿瘤剂又作为抑制肿瘤血管形成的抗血管生成剂的试剂。因此，可以控制原发性肿瘤和远处转移性肿瘤的基因可以是癌症治疗的有效治疗剂。其中一种新发现的分子是黑色素瘤分化相关基因-7（mda-7），也称为白细胞介素-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充分的证明。初步研究表明，MDA-7/IL-24蛋白被分泌（sMDA-7/IL-24）并抑制内皮细胞或毛细血管“管”样结构，这是血管生成的体外相关物。基于这些初步观察，我们假设sMDA-7/IL-24具有抗血管生成活性。为了进一步检验我们的假设，拟议的研究将集中在以下四个具体目标： 目的1：研究sMDA-7/IL-24对体外培养的内皮细胞的抗血管生成作用。 目的2：探讨sMDA-7/IL-24的抗血管生成活性是否是受体介导的。 目的3：探讨sMDA-7/IL-24抑制血管生成的机制。 目的4：评价sMDA-7/IL-24在肿瘤模型研究中的体内功效。本实验设计将使用分子和细胞模型来评估抗血管生成活性。 本提案中设计的实验将证明sMDA-7/IL-24具有有效的抗血管生成活性，并将为进一步开发mda-7作为最终转化为临床的抗癌治疗剂提供基础。

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.