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

评估 mda-7/IL-24 的抗血管生成特性

• 批准号: 7101896
• 负责人: Rajagopal Ramesh
• 金额: $ 21.78万
• 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: 2004-08-05 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101896
• 关键词: SCID mouse; angiogenesis inhibitors; antineoplastics; apoptosis; athymic mouse; biotherapeutic agent; cell differentiation; cell line; cell migration; cell proliferation; clinical research; cytokine; cytokine receptors; drug screening /evaluation; lung neoplasms; metastasis; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; pharmacokinetics; receptor expression; transcription factor; vascular endothelium

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.

描述（由申请人提供）：肺癌是全世界死亡的主要原因。据估计，美国每年将诊断出 175,000 例新肺癌病例，导致每年超过 157,000 例肺癌死亡。尽管肺癌的治疗策略取得了进步，但总体生存率仍不足 6 个月。这是由于无法控制肿瘤的局部扩散以及无法治疗已转移到远处部位的肿瘤。因此，迫切需要开发一种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的治疗方法。因此，需要新的治疗方式。一种这样的新颖的治疗方法是利用既作为靶向肿瘤的抗肿瘤剂又作为针对抑制肿瘤血管化的抗血管生成剂的作用的药剂。因此，能够控制原发肿瘤和远处转移肿瘤的基因可以成为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 基因针对一系列癌细胞的抗肿瘤活性在体外和体内都有充分记录。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”状结构，这是血管生成的体外相关性。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，拟议的研究将侧重于以下四个具体目标： 目标 1：体外研究 sMDA-7/IL-24 对内皮细胞的抗血管生成活性。 目标 2：研究 sMDA-7/IL-24 的抗血管生成活性是否是受体介导的。 目标 3：评估 sMDA-7/IL-24 抑制血管生成的机制。 目标 4：评估 sMDA-7/IL-24 在肿瘤模型研究中的体内功效。本提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 作为抗癌治疗剂奠定基础，最终转化为临床。