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）：基础分子机制 导致乳腺癌的进展和维持恶性肿瘤 表型可能涉及生长因子触发的信号传导级联反应 丝氨酸蛋白酶的激活。例如，EGF的过表达和 HER2受体和尿激酶纤溶酶原激活剂（UPA）经常是 与积极的临床过程相关，无病生存较短 时期，预后不良，人类乳腺癌的转移增加。更多的 最近，这里的gulin（HRG）是HER3和HER4受体的组合配体， 已被确定为预测预后不良的独立标记。 近年来，涉及干扰和/或阻塞的方法 抗受体mAB的染色体介导的自分泌/旁分泌生长刺激具有 是控制乳腺癌生长的主题 细胞增殖。人源化的MAB 225（C225）和MAB 4D5（Herceptin）是 目前正在II期和III期多中心临床试验中 与其他抗癌剂结合使用。至于尿激酶，因为 尿激酶纤溶酶原活化剂（UPA）依赖性周围的激活 蛋白水解和侵袭取决于UPA对其受体的定位， UPAR，阻止这种相互作用也可能导致肿瘤的抑制 进展和血管生成。 我们在这里目的是研究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）的临床功效或 与C225或Herceptin结合抑制乳腺癌的进展 更多侵入性表型。 我们的工作假设是“自分泌或旁分泌激活 UPA/UPAR系统或HRG或两者都有促进细胞周围侵袭 乳腺癌细胞；这条途径可能会受到的积极影响 通过间充质生长对HER2和EGFR的反式激活 因子HRG；而A36和Herceptin或C225的目标是UPA/UPAR可能 抑制乳腺癌的进展。” 该提案背后的理由是基于最近做出的观察 由（i）HRG刺激的主要研究员和同事 UPA/UPAR和入侵的表达和激活； （ii）特定的UPAR 抑制剂（A36）阻止了HRG介导的侵袭； （iii）A36抑制了VEGF 激活UPA/UPAR的乳腺癌细胞中的启动子活性； （iv）A36 抑制内皮细胞管的形成； （v）C225和赫赛汀阻止了 EGFR水平正常的浸润性乳腺癌细胞中的UPAR表达 和Her2； （vi）HRG过表达与短暂的无病相关 乳腺癌患者的生存。我们相信HRG，一个间充质 生长因子，可能在UPAR对肿瘤上的上调中起重要作用 通过启动细胞以最终激活UPA的UPA-UPAR级联 来自基质细胞，将UPAR拮抗剂A36与抗受体组合 MAB可以增强体内抗侵入性和抗血管生成特性/活性。 该提案的具体目的是：（1）确定分子 HRG和她的调节UPA/UPAR系统的机制； （2）至 检查A36和Herceptin或C225在体外临床前的影响 动物转移研究； （3）检查UPA/UPAR的重要性 与HRG作为人类乳腺癌的预后因素的关系。一个独特的方面 我们的建议是划定HRG调节UPA/UPAR的机制 和入侵，这将为转移性治疗提供新的理由 UPAR抑制剂和抗受体mabs Herceptin或C225的人类乳腺肿瘤。 这些结果将直接影响开发新型治疗性 干预策略。