ANTI-METALLOPROTEASE THERAPY

抗金属蛋白酶疗法

• 批准号: 6499556
• 负责人: ROBERT B. DICKSON
• 金额: $ 13.53万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-14 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6499556
• 关键词: angiogenesis; antineoplastics; ascites; biopsy; bryostatin; clinical trials; combination chemotherapy; disease /disorder model; drug interactions; drug screening /evaluation; enzyme linked immunosorbent assay; human subject; human therapy evaluation; hydroxamate; inhibitor /antagonist; laboratory mouse; lactones; lymph nodes; metalloendopeptidases; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer invasiveness; nonhuman therapy evaluation; protease inhibitor; protein kinase C

Recent studies by many investigators have identified representatives of all four major classes of proteases in breast cancer. However, the exact roles of these proteases in tumor angiogenesis growth, and metastasis are not yet clarified. We hypothesize that the matrix metalloproteases (including MMP-1, MMP-2, and MMP-9) play a pivotal role in tumor invasion and metastasis. We also propose that the serine/thyronine protein kinase family termed PKC is also important in this process due, at least in part, to its regulation of MMP synthesis and secretion. To test these ideas we will continue our study of a high affinity hydroxylamate inhibitor of MMP catalytic activity (termed BB-94, Batimastat) and a high affinity macrocyclic lactone inhibitor of PKC-induced MMP syntheses (bryostatin-1). We will carry out integrated studies of these two drugs in early phase clinical trials and in several experimental animal model systems of breast tumor growth, angiogenesis, invasion, lymph node and lung metastasis, and ascites invasion-late stage survival. In these studies, MMP levels and degree of catalytic activation will be monitored in plasma, pleural/ascites fluids, and in tumor biopsies for biochemical evidence of drug effectiveness. We will also further develop studies demonstrating a favorable interaction of BB-94 with bryostatin-l and of both agents with certain chemotherapeutic agents in our animal models. Interactions of BB-94 and bryostatin-l with retinoids and certain antiangiogenic drugs will also be examined as collaborations with two other projects in this application; retinoids are also known to suppress MMP synthesis. Evidence of favorable interactions in vivo with any of these strategies will lead to design of additional early phase clinical trials in the latter years of this proposal. Finally, we will explore proteolysis-associated mechanisms of treatment failure in animal models and patient trials. Plasma, ascites, and tumor biopsies in breast cancers undergoing treatment-associated failure will be evaluated for upregulated or activated MMPs, upregulation of urokinase (UPA) and increases in a novel 80kDa MMP-like enzyme which we have recently described. Regulation of protease inhibitors will also be evaluated. In summary, this project focusses on MMPs as therapeutic targets in breast cancer, establishes the potential for favorable interactions of antiMMP therapies with conventional chemotherapy and with other new biological therapies, and evaluates the role of further disregulated production of proteases in treatment failure.

许多研究人员的最新研究确定了 乳腺癌中的所有四种主要类别。但是，确切的 这些蛋白酶在肿瘤血管生成生长和转移中的作用是 尚未澄清。我们假设基质金属蛋白酶 （包括MMP-1，MMP-2和MMP-9）在肿瘤入侵中起关键作用 和转移。我们还提出丝氨酸/硫代蛋白激酶 在此过程中，称为PKC的家庭也很重要，至少在 部分，其调节MMP合成和分泌。测试这些 想法我们将继续研究高亲和力羟胺 MMP催化活性的抑制剂（称为BB-94，Batimastat）和高度 PKC诱导的MMP合成的亲和力大环内酯抑制剂 （Bryostatin-1）。我们将对这两种药物进行综合研究 在早期临床试验和几种实验动物模型中 乳腺肿瘤生长，血管生成，侵袭，淋巴结和 肺转移和​​腹水入侵阶段的生存。在这些 将监测研究，MMP水平和催化激活程度 在血浆，胸膜/腹水流体和肿瘤活检中 药物有效性的证据。我们还将进一步发展研究 证明了BB-94与Bryostatin-L和 两种药物在我们的动物模型中都有某些化学治疗剂。 BB-94和Bryostatin-L与类维生素的相互作用以及某些 抗血管生成药物也将作为与两种的合作 此应用程序中的其他项目；类视网膜类似也可以抑制 MMP合成。体内有利相互作用的证据 这些策略将导致设计其他早期临床 该提案后期的审判。最后，我们将探索 动物模型中治疗失败的蛋白水解相关机制 和患者试验。乳腺癌中的血浆，腹水和肿瘤活检 将评估与治疗相关的失败的上调 或激活的MMP，尿蛋白酶（UPA）的上调，并增加 我们最近描述的新型80KDA MMP样酶。规定 还将评估蛋白酶抑制剂的。总之，这个项目 专注于MMP作为乳腺癌的治疗靶标的，建立 抗AntiMMP疗法与 常规化疗以及其他新的生物疗法，以及 评估蛋白酶在 治疗失败。