Exploiting Novel Pathways to Treat Pancreatic Cancer

描述(申请人提供)：胰腺癌是最致命的癌症之一，因为它广泛侵犯周围组织并转移到远处器官，即使在肿瘤进展的早期也是如此。这种恶性肿瘤的预后不佳也反映了对当前治疗的普遍反应不佳。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。胰腺癌的特点是细胞外基质广泛沉积，这会对细胞行为产生深远的影响。我们的初步研究表明，胰腺癌来源的细胞在体外对外源性I型胶原的反应是通过经历从不活动的上皮细胞到高运动性和侵袭性的间充质细胞的转变。上皮向间充质转化的一个特征是N-钙粘蛋白的表达增加，我们和其他人已经证明了一种促进肿瘤细胞侵袭的蛋白质。对目前的研究方案特别重要的是，超过50%的侵袭性胰腺肿瘤表达N-钙粘附素。最近的研究表明，由Adherex Technologies，Inc.，Durham，NC开发的N-钙粘素拮抗剂ADH-1在体外和体内都能抑制N-钙粘蛋白的活性。我们最近发现ADH-1能够抑制N-钙粘附素诱导的肿瘤细胞的运动，并提出ADH-1与标准护理相结合将减缓胰腺癌的进展。我们将在侵袭性胰腺癌的小鼠模型中测试这一假设。此外，我们还鉴定了I型胶原下游促进N-钙粘蛋白上调和侵袭的信号通路，并建议测试该通路中不同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-钙粘附素的胰腺癌比表达N-钙粘附素的肿瘤更具侵袭性和转移性。在这里，我们将确定促进N-钙粘附素在胰腺癌中表达的途径，并检验阻断N-钙粘附素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。

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.