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

胰腺腺癌是最致命的癌症之一，因为它们广泛地侵袭到胰腺组织中。 周围组织和远处器官转移，即使在肿瘤进展的早期阶段。穷人 这种恶性肿瘤的预后也反映了对目前治疗的反应通常较差。因此，基本的 了解这些肿瘤的生物学和促进其侵袭的机制， 转移将为开发新的诊断和治疗方法提供基础。 胰腺癌的特征是细胞外基质的广泛沉积， 对细胞行为有着深远的影响。我们有初步的研究表明， 胰腺癌在体外对外源性I型胶原的反应是通过转化 从一个不活动的上皮细胞到一个高度活动和侵袭性的间充质细胞。上皮细胞的标志， 间充质转化是N-钙粘蛋白的表达增加，我们和其他人已经证明了这种蛋白质 促进肿瘤细胞侵袭。对目前的建议特别重要的是，N-钙粘蛋白表达为 超过50%的侵袭性胰腺肿瘤。 最近的研究表明，由Adherex Technologies开发的N-钙粘蛋白拮抗剂Exherin？， Inc.达勒姆，NC，在体外和体内抑制N-钙粘蛋白的活性。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，并提出在N-钙粘蛋白中检验这一假设， 在细胞运动性的组织培养模型和小鼠模型中表达胰腺癌细胞 侵袭性胰腺癌。此外，我们建议表征下游的信号通路， 胶原蛋白I，其促进N-钙粘蛋白的上调和侵袭，用于鉴定潜在的 可与Exherin联合治疗的抑制剂。最后，我们将测试 Exherin作为临床试验中的人类胰腺癌治疗。

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.