Exploiting Novel Pathways to Treat Pancreatic Cancer

描述（由申请人提供）：胰腺腺癌是最致命的癌症之一，因为它们广泛侵袭周围组织并转移到远处器官，即使在肿瘤进展的早期阶段。这种恶性肿瘤的不良预后也反映了对当前治疗的普遍不良反应。因此，对这些肿瘤的生物学和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。胰腺腺癌的特点是细胞外基质的广泛沉积，这对细胞行为有深远的影响。我们的初步研究表明，胰腺腺癌细胞通过从非运动上皮细胞向高度运动和侵袭性间充质细胞的转化，在体外对外源性I型胶原有反应。上皮细胞向间充质细胞转变的一个标志是n -钙粘蛋白的表达增加，我们和其他人已经证明了这种蛋白可以促进肿瘤细胞的侵袭。N-cadherin在超过50%的侵袭性胰腺肿瘤中表达，这对目前的提议具有特别的意义。最近的研究表明，n -钙粘蛋白拮抗剂ADH-1由Adherex技术公司开发。Durham， 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n- cadherin诱导的肿瘤细胞运动，并提出ADH-1与标准护理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验证这一假设。此外，我们描述了I型胶原下游促进N-cadherin上调和侵袭的信号通路，并提出测试该通路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-cadherin的胰腺癌比没有N-cadherin的肿瘤更具侵袭性和转移性。在这里，我们将确定促进N-cadherin在胰腺癌中表达的途径，并验证阻断N-cadherin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.