Genetically Engineered PAI1 for Anti-cancer Therapy

用于抗癌治疗的基因工程 PAI1

• 批准号: 6817045
• 负责人: JERZY JANKUN
• 金额: $ 13.35万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6817045
• 关键词: SCID mouse; SDS polyacrylamide gel electrophoresis; X ray crystallography; angiogenesis inhibitors; antineoplastics; biotechnology; biotherapeutic agent; cell line; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; gene mutation; pharmacokinetics; plasminogen activator inhibitors; prostate neoplasms; protein binding; protein engineering; recombinant proteins; urokinase; vitronectin

DESCRIPTION (provided by applicant): Proteolytic activity driven by urokinase plasminogen activator (uPA) is commonly recognized as a critical factor in metastasis. Reduction of proteolytic activity has been proposed as a cancer treatment option; uPA inhibitors could be utilized as a cancer treatment if used prior to the onset of the metastatic process. Moreover, uPA inhibitors have been recently shown to reduce tumor growth as well. We have found that uPA inhibitors reduce angiogenesis (uPA is overexpressed on tip of capillary vessels) and thereby reduce tumor size. The ultimate goal of this proposal is to identify novel inhibitors of uPA suitable for cancer treatment. In this study we want make use of plasminogen activator inhibitor (PAI-1), which will be genetically engineered to introduce novel and desired properties to this protein. These properties include: long half-life (wild PAI-1 converts into its latent form in approximately 2h), lack of vitronectin binding capability (PAI-1 binds to this protein and this property could increase motility of cancer cells), and uPA specificity (PAI-1 is a non-specific inhibitor of both uPA and tPA). The urokinase is involved in pericellular malignant proteolysis, while tPA mainly mediates physiologically needed intravascular thrombolysis and that function ought to be preserved. Lastly, these altered forms of PAI-1 will be combined and tested for anti-uPA and anti-angiogenic activity. The metastatic process and angiogenesis are driven by the urokinase plasminogen system and matrix metallo proteinases (MMPs). In some clinical studies of advanced cancers, inhibition of MMPs showed promise, while in other studies they did not. The efficacy of anti-angiogenic agents would probably be best in remission after traditional chemotherapy, or in combination with cytotoxic agents and possibly with combinations of urokinase and MMPs inhibitors. In addition, the best results can perhaps be gained in adjuvant therapy or in early stages of cancer, when the tumor burden is minimal. Our future efforts are directed toward these goals.

描述（由申请人提供）：由尿激酶纤溶酶原激活剂（uPA）驱动的蛋白水解活性通常被认为是转移的关键因素。降低蛋白水解活性已被提议作为一种癌症治疗选择；如果在转移过程开始之前使用 uPA 抑制剂，则可用作癌症治疗方法。此外，uPA 抑制剂最近已被证明可以减少肿瘤生长。我们发现 uPA 抑制剂可减少血管生成（uPA 在毛细血管尖端过度表达），从而缩小肿瘤大小。 该提案的最终目标是确定适合癌症治疗的新型 uPA 抑制剂。在这项研究中，我们希望利用纤溶酶原激活剂抑制剂 (PAI-1)，它将经过基因工程改造，为这种蛋白质引入新颖且所需的特性。这些特性包括：半衰期长（野生 PAI-1 在大约 2 小时内转化为潜伏形式）、缺乏玻连蛋白结合能力（PAI-1 与该蛋白结合，这种特性可以增加癌细胞的运动性）以及 uPA 特异性（PAI-1 是 uPA 和 tPA 的非特异性抑制剂）。尿激酶参与细胞周恶性蛋白水解，而tPA主要介导生理需要的血管内溶栓，并且应该保留该功能。最后，这些改变形式的 PAI-1 将被组合并测试其抗 uPA 和抗血管生成活性。 转移过程和血管生成由尿激酶纤溶酶原系统和基质金属蛋白酶（MMP）驱动。在一些晚期癌症的临床研究中，MMP 的抑制显示出了希望，而在其他研究中却没有。抗血管生成药物的疗效可能在传统化疗后缓解时效果最佳，或与细胞毒性药物联合使用，并可能与尿激酶和 MMP 抑制剂联合使用。此外，当肿瘤负荷最小时，辅助治疗或癌症早期阶段可能会获得最佳结果。我们未来的努力就是为了实现这些目标。