Exploiting Novel Pathways to Treat Pancreatic Cancer

探索治疗胰腺癌的新途径

• 批准号: 7571462
• 负责人: KEITH R JOHNSON
• 金额: $ 16.34万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571462
• 关键词: Benign; Cadherins; Cells; Clinical Research; Clinical Treatment; Collagen; Collagen Receptors; Collagen Type I; Combined Modality Therapy; DDR1 gene; Data; Deposition; Diagnosis; Disease; Distant; E-Cadherin; Effectiveness; Epithelial Cells; Extracellular Matrix; Growth; Human; In Vitro; Integrins; Lead; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mesenchymal; Methods; N-Cadherin; Neoplasm Metastasis; Organ; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Proteins; Role; SP600125; Signal Pathway; Signal Transduction; Staging; Technology; Testing; Tissues; Tumor Biology; Tumor Cell Invasion; Up-Regulation; base; cancer cell; cell behavior; cell growth; cell motility; epithelial to mesenchymal transition; gemcitabine; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; novel; outcome forecast; pancreatic neoplasm; prevent; public health relevance; response; standard of care; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): 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, ADH-1 developed by Adherex Technologies, Inc. Durham, NC, inhibits the activity of N-cadherin in vitro and in vivo. We have recently shown that ADH-1 is capable of inhibiting N-cadherin-induced motility in tumor cells, and propose that ADH-1 in combination with the standard of care will reduce pancreatic cancer progression. We will test this hypothesis in a mouse model of invasive pancreatic cancer. In addition, we have characterized the signaling pathways downstream of collagen I that promote up-regulation of N-cadherin and invasion, and propose to test potential inhibitors of various nodes in this pathway for their capability to inhibit pancreatic cancer progression. Public Health Relevance: N-cadherin-expressing pancreatic cancers are more aggressive and more metastatic than N-cadherin null tumors. Here we will identify pathways that promote N-cadherin expression in pancreatic cancers and test the hypothesis that blocking N-cadherin function will limit tumor growth and invasion. Our studies are highly likely to lead to new clinical treatments for human pancreatic cancer.

描述（由申请人提供）：胰腺腺癌是最致命的癌症之一，因为它们广泛侵入周围组织并转移到远处器官，即使在肿瘤进展的早期阶段。这种恶性肿瘤的预后差也反映了对目前治疗的反应普遍较差。因此，对这些肿瘤的生物学以及促进其侵袭和转移的机制的基本了解将为开发新的诊断和治疗方法提供基础。胰腺癌的特征在于细胞外基质的广泛沉积，其可对细胞行为产生深远影响。我们有初步的研究表明，来自胰腺癌的细胞在体外响应于外源性I型胶原蛋白，通过经历从非运动性上皮细胞到高度运动性和侵袭性间充质细胞的转化。上皮细胞向间充质细胞转化的一个标志是N-钙粘蛋白的表达增加，我们和其他人已经证明这种蛋白质促进肿瘤细胞的侵袭。对目前的建议特别重要的是，超过50%的侵袭性胰腺肿瘤表达N-钙粘蛋白。最近的研究表明，由Adherex Technologies，Inc.达勒姆，NC，在体外和体内抑制N-钙粘蛋白的活性。我们最近发现ADH-1能够抑制肿瘤细胞中N-钙粘蛋白诱导的运动，并提出ADH-1与标准治疗相结合将减少胰腺癌的进展。我们将在侵袭性胰腺癌的小鼠模型中检验这一假设。此外，我们已经表征了促进N-钙粘蛋白上调和侵袭的I型胶原蛋白下游的信号传导途径，并建议测试该途径中各种节点的潜在抑制剂抑制胰腺癌进展的能力。公共卫生相关性：表达N-钙粘蛋白的胰腺癌比无N-钙粘蛋白的肿瘤更具侵袭性和转移性。在这里，我们将确定促进胰腺癌中N-钙粘蛋白表达的途径，并测试阻断N-钙粘蛋白功能将限制肿瘤生长和侵袭的假设。我们的研究极有可能为人类胰腺癌带来新的临床治疗方法。