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）：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方案；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，uPA抑制剂最近也被证明可以减少肿瘤的生长。我们发现uPA抑制剂减少血管生成（uPA在毛细血管尖端过度表达），从而减小肿瘤大小。