Inhibition of a proteinase involved in tumor invasion

描述（由申请人提供）： 胰腺癌是第四和第五最常见的癌症相关的原因 在美国，男性和女性的死亡率分别为。 检测是 通常只在疾病的晚期观察到;因此， 患者在确诊时，情况非常糟糕。 作为唯一的治疗性干预 是早期手术，延迟检测， 患者在疾病确诊后不到10%， 存活率可以忽略不计。 胰腺癌也是 其特征在于其侵袭性和转移性。 的过程 肿瘤转移是由一系列复杂的事件组成的。 之一 肿瘤细胞侵袭的最初步骤是基底膜的降解， 椎板和周围组织的局部浸润。 侵袭和转移 因此依赖于所产生的多种降解酶的作用 由肿瘤细胞本身或宿主组织的细胞引起。 符合 这一概念，在恶性组织中蛋白酶活性的增加 与对照组织相比， 我们发现金属蛋白酶meprin 在胰腺肿瘤中表达，但在正常胰腺组织中不表达。 梅普林斯 已经显示降解细胞外基质成分。 使用稳定细胞 我们已经发现，表达 在体外侵袭测定中增加细胞的侵袭力。 基于这些观察，我们假设meprin参与了 胰腺肿瘤的侵袭和转移，并可作为靶点， 治疗干预 因此，该项目的目标是准备 抑制meprin的蛋白水解活性并检测其活性的试剂 抑制体外细胞侵袭的能力。 成功完成这些 研究将进一步验证这些蛋白酶作为靶点， 治疗这种致命的肿瘤。 在这项研究中，我们建议 具体目的如下：1）鉴定甲氨蝶呤的肽抑制剂 活性，和2）获得小鼠单克隆抗体 抑制肿瘤细胞侵袭的抗人meprin。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth and fifth most common cause of cancer-related deaths in men and women, respectively, in the United States. Detection is normally observed only in late stages of the disease; thus, prognosis of patients upon diagnosis is extremely poor. As the only curative intervention is early surgery, with delayed detection the one-year survival rate of patients is less than 10% after the disease has been diagnosed and the 5-year survival rate is negligible. Carcinomas of the pancreas are also characterized by their aggressive invasiveness and metastasis. The process by which neoplasms metastasize is composed of a complex series of events. One of the initial steps in tumor cell invasion is the degradation of the basal lamina and local invasion of the surrounding tissue. Invasion and metastasis is thus dependent upon the action of a variety of degradative enzymes produced by the tumor cells themselves or cells of the host tissue. Consistent with this notion, increased amounts of proteinase activities in malignant tissues as compared with control tissues have been reported. We have made the novel observation that the metalloproteinase meprin is expressed in pancreatic tumors but not in normal pancreatic tissues. Meprins have been shown to degrade extracellular matrix components. Using stable cell lines generated to express recombinant meprin , we have found that expression of meprin increases the invasiveness of cells in invasion assays in vitro. Based on these observations, we hypothesize that meprin is involved in pancreatic tumor invasion and metastasis and may serve as a target for therapeutic intervention. The goal of this project, therefore, is to prepare reagents to inhibit the proteolytic activity of meprin and to examine their ability to inhibit in vitro cell invasion. The successful completion of these studies would provide further validation of these proteases as targets for therapeutic intervention for this deadly neoplasm. In this study, we propose the following specific aims: 1) to identify peptide inhibitors of meprin activity using phage display and 2) to obtain mouse monoclonal antibodies against human meprin that inhibit tumor cell invasion.