Biomarkers of COX-2 inhibitors in intraductal papillary mucinous neoplasm (IPMN)

描述(由申请人提供)：为胰腺癌找到成功的化疗方法的努力令人失望。一些患者患胰腺癌的风险增加，或者可能有胰腺癌前病变，这使他们易于在以后发展为胰腺癌。在这些患者中，化学预防措施可能会阻止胰腺癌的未来发展。胰腺导管内乳头状黏液性肿瘤(IPMN)是胰腺癌的先兆。这些癌前病变在胰腺导管系统内形成，并分泌一种粘液物质。IPMN的恶性潜能被认为是其不典型增生程度的函数。我们的初步数据表明，COX-2的表达和活性(PGE2水平)可能确实与不典型增生的程度有关。环氧合酶-2似乎在胰腺肿瘤的发生中起着重要作用。COX-2抑制剂在IPMN中的作用尚未确定。我们正在对IPMN患者进行塞来昔布(COX-2抑制剂)的生物标记物研究。由于IPMN是导管内病变，我们建议在塞来昔布治疗前后检测IPMN活检和胰管液，以确定COX-2抑制剂对COX-2活性(PGE2水平)、COX-2表达、发育不良分期以及增殖、凋亡和血管生成指数的影响。我们还将通过细胞阻断/免疫细胞化学、ELISA法和SELDI研究塞来昔布对IPMN恶性进展新标记物表达的影响。重要的是，这些研究可能为环氧合酶-2抑制剂的多机构研究提供临床证据，用于IPMN患者和其他胰腺癌前病变患者的化学预防，这些患者具有发展为胰腺癌的高风险。

DESCRIPTION (provided by applicant): Efforts at finding a successful chemotherapy for pancreatic cancer have been disappointing. Some patients are at increased risk of pancreatic cancer or may have pre-malignant pancreatic lesions which predispose them to later pancreatic cancer development. In these individuals, chemopreventative measures may block future development of pancreatic cancer. Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are precursors of pancreatic cancer. These precancerous lesions form inside the pancreatic ductal system and secrete a mucinous material. The malignant potential of IPMNs is thought to be a function of their degree of dysplasia. Our preliminary data suggests COX-2 expression and activity (PGE2 level) may indeed be associated with degree of dysplasia. Cyclooxygenase-2 appears to play a significant role in pancreatic tumorigenesis. The role of COX-2 inhibitors in IPMN has not been determined. We are conducting a biomarker study of celecoxib (COX-2 inhibitor) in patients with IPMN. Since IPMNs are intraductal lesions, we propose to examine IPMN biopsies and pancreatic ductal fluid pre- and post-celecoxib treatment to determine the effect of COX-2 inhibitors on COX-2 activity (PGE2 levels), COX-2 expression, dysplastic stage, and indices of proliferation, apoptosis and angiogenesis. We will also investigate celecoxib's effects on the expression of novel markers of IPMN malignant progression by cell block/immunocytochemistry ELISA and SELDI. Importantly, these studies may provide clinical evidence in support of a multi-institutional study of COX-2 inhibitors for chemoprevention in patients with IPMN and other precancerous pancreatic lesions at high risk for the development of pancreatic cancer.