Proteases in Prostate Cancer Bone Metastasis

前列腺癌骨转移中的蛋白酶

• 批准号: 6803138
• 负责人: MICHAEL L CHER
• 金额: $ 42.71万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-25 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803138
• 关键词: SCID mouse; biopsy; bone; bone marrow; bone neoplasms; clinical research; confocal scanning microscopy; disease /disorder model; endopeptidases; enzyme activity; enzyme substrate; fluorescent dye /probe; gene expression; genetically modified animals; human subject; in situ hybridization; laboratory mouse; metastasis; model design /development; neoplasm /cancer genetics; pathologic bone resorption; patient oriented research; prostate neoplasms; protease inhibitor; proteolysis; time resolved data

DESCRIPTION (provided by applicant): In prostate cancer, proteases are well known to regulate cell proliferation and death, tumor invasion, metastasis, and angiogenesis. Proteolysis is also essential for normal and tumor-induced bone remodeling. Although protease inhibitors have been tested in some patients with cancer, none have entered into clinical trials specifically for patients with bone metastasis. We must apply a broad and comprehensive strategy to choose the appropriate protease targets specific for bone metastasis, and we must improve our understanding of the interplay between tumor cells and bone with regard to protease activity in the bone microenvironment. We must also develop systems for monitoring the inhibition of proteases as a key endpoint in clinical trials. Therefore, our Specific Aims are to: (1) Analyze the effects of prostate tumor cell-bone interactions on the proteolysis associated with prostate cancer bone metastases; (2) confirm that the proteases identified in the organotypic model system of Aim 1 are expressed and active during the colonization of bone by prostate cancer cells in vivo; (3) validate that the protease classes and individual proteases identified above contribute to the proteolysis induced by prostate tumor cell-bone interactions; and (4) use protease-activated probes to image both activities of proteases validated as contributing to prostate cancer bone metastasis as well as the abrogation of those activities by protease inhibitors. To accomplish these goals will use novel bone organotypic models, bone metastasis models, and clinical human bone metastasis tissues. Gene profiling methods will be used to monitor changes in protease gene expression in tumor and bone marrow stromal cells. Prostate cancer-induced proteolysis of bone or relevant substrates will be monitored, and a variety of methods will be used to measure and visualize activity of individual proteases. The roles of specific stromal-derived proteases in bone metastasis models will be examined using general and specific protease inhibitors and as well as cells, bones, and mice rendered genetically null for specific proteases. As clinical trials with protease inhibitors will be more informative if protease activity can be monitored non-invasively, we will validate protease-activated imaging probes for their ability to selectively image protease activity and its abrogation by protease inhibitors in both in vitro and in vivo models of prostate cancer bone metastasis.

描述（由申请人提供）： 在前列腺癌中，众所周知蛋白酶调节细胞增殖和死亡、肿瘤侵袭、转移和血管生成。蛋白水解对于正常和肿瘤诱导的骨重建也是必不可少的。虽然蛋白酶抑制剂已经在一些癌症患者中进行了测试，但没有一种药物进入专门针对骨转移患者的临床试验。我们必须应用广泛而全面的策略来选择适当的蛋白酶靶点，特异性骨转移，我们必须提高我们对肿瘤细胞和骨之间的相互作用的理解，在骨微环境中的蛋白酶活性。我们还必须开发用于监测蛋白酶抑制的系统，作为临床试验的关键终点。因此，我们的具体目标是：（1）分析前列腺肿瘤细胞-骨相互作用对与前列腺癌骨转移相关的蛋白质水解的影响;（2）确认Aim 1的器官型模型系统中鉴定的蛋白酶在前列腺癌细胞体内骨定殖期间表达并活跃;（3）验证以上鉴定的蛋白酶类别和单独的蛋白酶有助于由前列腺肿瘤细胞-骨相互作用诱导的蛋白水解;和（4）使用蛋白酶激活的探针来对经验证有助于前列腺癌骨转移的蛋白酶的活性以及蛋白酶抑制剂对这些活性的消除进行成像。为了实现这些目标，将使用新的骨器官型模型、骨转移模型和临床人骨转移组织。基因分析方法将用于监测肿瘤和骨髓基质细胞中蛋白酶基因表达的变化。将监测前列腺癌诱导的骨或相关底物的蛋白水解，并将使用各种方法测量和可视化单个蛋白酶的活性。将使用一般和特异性蛋白酶抑制剂以及使特异性蛋白酶遗传无效的细胞、骨和小鼠来检查特异性基质衍生蛋白酶在骨转移模型中的作用。由于蛋白酶抑制剂的临床试验将提供更多信息，如果蛋白酶活性可以非侵入性监测，我们将验证蛋白酶激活成像探针的能力，选择性地成像蛋白酶活性和蛋白酶抑制剂在体外和体内前列腺癌骨转移模型中的废除。