Targeting Urokinase Pathway for Breast Cancer Therapy

针对乳腺癌治疗的尿激酶通路

• 批准号: 6514790
• 负责人: RAKESH KUMAR
• 金额: $ 31.13万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514790
• 关键词: SCID mouse; antineoplastics; antireceptor antibody; athymic mouse; breast neoplasms; clinical trial phase I; combination cancer therapy; cyclic peptides; enzyme inhibitors; epidermal growth factor; female; growth factor receptors; heregulin; human subject; human therapy evaluation; metastasis; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; patient oriented research; phosphatidylinositol 3 kinase; urokinase; vascular endothelial growth factors; women's health

DESCRIPTION (provided by applicant): The underlying molecular mechanisms leading to breast cancer progression and maintenance of the malignant phenotypes may involve a growth factor-triggered signaling cascade leading to the activation of serine proteases. For example, overexpression of the EGF and HER2 receptors, and urokinase plasminogen activator (uPA) are frequently associated with an aggressive clinical course, shorter disease-free survival periods, poor prognosis, and increased metastasis in human breast cancer. More recently heregulin (HRG), a combinational ligand for HER3 and HER4 receptors, has been identified as an independent marker that predicts poor prognosis. In recent years, approaches involving interference with and/or blocking of HER-mediated autocrine/paracrine growth stimulation by anti-receptor mAbs have been the subject of active investigation to control the growth of breast cancer cell proliferation. Humanized mAb 225 (C225) and mAb 4D5 (Herceptin) are currently in phase II and phase III multicenter clinical trials, both alone and in combination with other anticancer agents. As for urokinase, because the activation of urokinase plasminogen activator (uPA)-dependent pericellular proteolysis and invasion depends on the localization of uPA to its receptor, uPAR, blocking this interaction may also lead to inhibition of tumor progression and angiogenesis. We purpose here to investigate the signaling pathways by which HRG regulates the expression and activation of the uPA/uPAR system, and to establish the clinical efficacy of a specific uPAR inhibitor (A36) either alone or in combination with C225 or Herceptin for suppressing breast cancer progression to more invasive phenotypes. Our working hypotheses are that "autocrine or paracrine activation of the uPA/uPAR system or HRG or both contributes to increased pericellular invasion of breast cancer cells; that this pathway may be positively influenced by the transactivation of HER2 and EGFR in tumor cells by the mesenchymal growth factor HRG; and that targeting uPA/uPAR with A36 and Herceptin or C225 may inhibit the progression of breast cancer." The rationale behind this proposal is based on the observations recently made by the Principal Investigator and colleagues that (i) HRG-stimulates the expression and activation of uPA/uPAR and invasion; (ii) a specific uPAR inhibitor (A36) blocked HRG-mediated invasion; (iii) A36 inhibited the VEGF promoter activity in breast cancer cells that have activated uPA/uPAR; (iv) A36 inhibited endothelial cell tube formation; (v) C225 and Herceptin blocked the uPAR expression in invasive breast cancer cells that have normal levels of EGFR and HER2; and (vi) HRG overexpression was associated with a short disease-free survival in patients with breast cancer. We believe that HRG, a mesenchymal growth factor, may have a significant role in the upregulation of uPAR on tumor cells by priming them for eventual activation of the uPA-uPAR cascade by uPA from stromal cells and combining the uPAR antagonist A36 with an anti-receptor mAb may enhance anti-invasive and anti-angiogenic properties/activity in vivo. The Specific Aims of this proposal are: (1) to determine the molecular mechanism by which HRG and the HERs regulate the uPA/uPAR system; (2) to examine the effects of A36 and Herceptin or C225 in preclinical in vitro and animals metastasis studies; and (3) to examine the significance of uPA/uPAR in relation to HRG as prognostic factors in human breast cancer. A unique aspect of our proposal is delineation of the mechanism by which HRG regulates uPA/uPAR and invasion, which will provide a novel rationale for therapy of metastatic human breast tumors by uPAR inhibitor and anti-receptor mAbs Herceptin or C225. These results will have a direct impact in developing novel therapeutic intervention strategies.

描述（由申请人提供）：潜在的分子机制 导致乳腺癌进展并维持恶性 表型可能涉及生长因子触发的信号级联反应，导致 丝氨酸蛋白酶的激活。例如，EGF 的过度表达和 HER2 受体和尿激酶纤溶酶原激活剂 (uPA) 经常 与侵袭性临床病程、较短的无病生存期相关 人类乳腺癌的周期、预后不良和转移增加。更多的 最近的heregulin (HRG)是HER3和HER4受体的组合配体， 已被确定为预测不良预后的独立标志物。 近年来，涉及干扰和/或阻止的方法 抗受体单克隆抗体介导的 HER 介导的自分泌/旁分泌生长刺激 是控制乳腺癌生长的积极研究的主题 细胞增殖。人源化 mAb 225 (C225) 和 mAb 4D5 (赫赛汀) 目前正在进行II期和III期多中心临床试验，无论是单独还是 与其他抗癌药物联合使用。至于尿激酶，因为 尿激酶纤溶酶原激活剂 (uPA) 依赖性细胞周的激活 蛋白水解和侵袭取决于 uPA 对其受体的定位， uPAR，阻断这种相互作用也可能导致肿瘤抑制 进展和血管生成。 我们的目的是研究 HRG 调节的信号通路 uPA/uPAR系统的表达和激活，并建立 特定 uPAR 抑制剂 (A36) 单独使用或联合使用的临床疗效 与 C225 或赫赛汀联合用于抑制乳腺癌进展 更具侵袭性的表型。 我们的工作假设是“自分泌或旁分泌激活 uPA/uPAR 系统或 HRG 或两者均有助于增加细胞周侵袭 乳腺癌细胞；该途径可能受到以下因素的积极影响 间充质生长对肿瘤细胞中 HER2 和 EGFR 的反式激活 HRG 因子；并且用 A36 和赫赛汀或 C225 靶向 uPA/uPAR 可能 抑制乳腺癌的进展。” 该提案背后的理由基于最近的观察 首席研究员和同事认为 (i) HRG 刺激了 uPA/uPAR 的表达和激活以及侵袭； (ii) 特定的uPAR 抑制剂 (A36) 阻断 HRG 介导的侵袭； (iii) A36 抑制 VEGF 已激活 uPA/uPAR 的乳腺癌细胞中的启动子活性； (四)A36 抑制内皮细胞管形成； (v) C225 和赫赛汀阻断 EGFR 水平正常的侵袭性乳腺癌细胞中 uPAR 表达 和 HER2； (vi) HRG 过度表达与短期无病期相关 乳腺癌患者的生存率。我们相信HRG是一种间充质细胞 生长因子，可能在肿瘤上调 uPAR 中起重要作用 通过启动细胞最终激活 uPA-uPAR 级联 来自基质细胞并将 uPAR 拮抗剂 A36 与抗受体结合 mAb 可增强体内抗侵入和抗血管生成特性/活性。 该提案的具体目标是：（1）确定分子 HRG 和 HER 调节 uPA/uPAR 系统的机制； (2) 至 检查 A36 和赫赛汀或 C225 在临床前体外的作用 动物转移研究； (3) 检验 uPA/uPAR 在 HRG 作为人类乳腺癌预后因素的关系。独特的一面 我们提案的重点是描述 HRG 调节 uPA/uPAR 的机制 和侵袭，这将为转移性肿瘤的治疗提供新的理论依据。 uPAR 抑制剂和抗受体单克隆抗体 Herceptin 或 C225 治疗人类乳腺肿瘤。 这些结果将对开发新的治疗方法产生直接影响 干预策略。