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中的关键因素。蛋白水解活性的降低已被认为是癌症治疗选择。如果在转移过程开始之前使用UPA抑制剂，则可以用作癌症治疗。此外，最近已证明UPA抑制剂也可以减少肿瘤的生长。我们发现UPA抑制剂减少了血管生成（UPA在毛细血管尖端过表达），从而减少肿瘤大小。 该提案的最终目标是确定适合癌症治疗的UPA的新型抑制剂。在这项研究中，我们希望利用纤溶酶原激活剂抑制剂（PAI-1），该抑制剂将经过基因设计，以将新颖和所需的特性引入该蛋白质。这些特性包括：长半衰期（野生PAI-1在大约2H中转化为潜在形式），缺乏玻璃连蛋白结合能力（PAI-1与该蛋白质结合，并且该特性可能会增加癌细胞的运动性），并且UPA特异性（PAI-1是UPA和TPA的非特异性抑制剂）。尿蛋白酶参与细胞周围恶性蛋白水解，而TPA主要介导生理所需的血管内溶栓，应保留该功能。最后，这些改变的PAI-1形式将合并并测试抗UPA和抗血管生成活性。 转移过程和血管生成是由尿激酶纤溶酶原系统和基质金属蛋白酶（MMP）驱动的。在一些对晚期癌症的临床研究中，对MMP的抑制作用显示出希望，而在其他研究中则没有。抗血管生成剂的功效可能是传统化疗后最好的缓解，或与细胞毒性剂结合使用，可能与尿激酶和MMPS抑制剂的组合结合使用。此外，当肿瘤负担很小时，也许可以在辅助治疗或癌症的早期阶段获得最佳结果。我们未来的努力是针对这些目标的。