P-2: Inhibitors of N-cahedrin in the treatment of pancreatic cancer

P-2：N-caedrin 抑制剂治疗胰腺癌

• 批准号: 8328170
• 负责人: KEITH R JOHNSON
• 金额: $ 15.76万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328170
• 关键词: Apoptosis; Attention; Benign; Biological Markers; Cadherins; Capillary Endothelial Cell; Cells; Chemicals; Clinic; Clinical; Clinical Research; Clinical Trials; Collagen; Collagen Type I; Combined Modality Therapy; Data; Deposition; Diagnosis; Distant; E-Cadherin; Endothelial Cells; Epithelial; Epithelial Cells; Extracellular Matrix; Growth; Human; In Vitro; Invaded; Lead; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mesenchymal; Methods; Modeling; Monitor; N-Cadherin; Neoplasm Metastasis; Organ; P-2; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Peritoneal; Phase I Clinical Trials; Proteins; Role; Safety; Signal Pathway; Staging; Technology; Testing; Tissues; Treatment Efficacy; Tumor Angiogenesis; Tumor Biology; Tumor Cell Invasion; Unresectable; Up-Regulation; Vascular blood supply; Vascularization; base; cell behavior; cell motility; design; efficacy testing; epithelial to mesenchymal transition; gemcitabine; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; outcome forecast; pancreatic cancer cells; pancreatic neoplasm; prevent; response; therapeutic target; tissue culture; tumor; tumor progression

Pancreatic adenocarcinomas are among the most fatal cancers because of their extensive invasion into surrounding tissues and metastasis to distant organs, even at an early stage of tumor progression. The poor prognosis of this malignancy also reflects a generally poor response to current therapies. Thus, a basic understanding of the biology of these tumors and the mechanisms that promote their invasion and metastasis will provide a basis for developing new methods for diagnosis and treatment. Pancreatic adenocarcinomas are characterized by extensive deposition of extracellular matrix, which can have profound effects on cell behavior. We have preliminary studies showing that cells derived from pancreatic adenocarcinomas respond in vitro to exogenous collagen type I by undergoing a transformation From a non-motile epithelial cell to a highly motile and invasive mesenchymal cell. A hallmark of epithelial to mesenchymal transitions is increased expression of N-cadherin, a protein we and others have shown promotes tumor cell invasion. Of particular significance to the current proposal, N-cadherin is expressed by more than 50% of invasive pancreatic tumors. Recent studies have shown that the N-cadherin antagonist, Exherin¿, developed by Adherex Technologies, Inc. Durham, NC, inhibits the activity of N-cadherin in vitro and in vivo. We hypothesize that Exherin¿ is capable of inhibiting N-cadherin-induced motility in tumor cells, and propose to test this hypothesis in Ncadherin- expressing pancreatic cancer cells in a tissue culture model of cell motility, and in a mouse model of invasive pancreatic cancer. In addition, we propose to characterize the signaling pathways downstream of collagen I that promote up-regulation of N-cadherin and invasion, for the purpose of identifying potential inhibitors that could be used in combination therapy with Exherin¿. Finally, we will test the efficacy of Exherin¿ as a treatment for human pancreatic cancer in clinical trials.

胰腺癌是最致命的癌症之一，因为它们广泛入侵 周围的组织和转移向遥远的器官，即使在肿瘤进展的早期阶段也是如此。穷人 这种恶性肿瘤的预后也反映出对当前疗法的反应总体不良。那，基本 了解这些肿瘤的生物学以及促进其侵袭的机制 转移将为开发新方法的诊断和治疗方法提供基础。 胰腺腺癌的特征是细胞外基质的广泛沉积，可以 对细胞行为有深远的影响。我们有初步研究表明，来自 胰腺腺癌在体外对I型胶原蛋白I型通过转变做出了反应 从非运动上皮细胞到高度运动和浸润性间充质细胞。上皮的标志 间充质转变是N-钙粘蛋白的表达增加，N-钙黏着蛋白和其他人已经显示 促进肿瘤细胞侵袭。 N-钙粘蛋白对当前建议特别重要，由 超过50％的侵入性胰腺肿瘤。 最近的研究表明，由Adherex Technologies开发的N-钙粘蛋白拮抗剂exherin？ 北卡罗来纳州达勒姆（Inc. Durham）Inc.抑制N-钙粘蛋白在体外和体内的活性。我们假设exherin？是 能够抑制肿瘤细胞中N-钙粘蛋白诱导的运动性，并提议在Ncadherin-- 在细胞运动的组织培养模型和小鼠模型中表达胰腺癌细胞 侵入性胰腺癌。此外，我们建议表征下游的信号通路 促进N-钙粘蛋白和入侵上调的胶原蛋白I，目的是确定潜力 可用于与雌雄同体组合疗法的抑制剂。最后，我们将测试 在临床试验中，Elexherin？作为人类胰腺癌的治疗方法。