The Cholecystokinin-C (CCK-C) Receptor for Early Detection of Pancreatic Cancer

描述(申请人提供)：胰腺癌是美国癌症相关死亡的第四大原因，五年存活率不到1%，仍然是所有恶性肿瘤中最低的。胰腺癌预后不佳的原因包括无法在早期诊断这种恶性肿瘤以及对标准化疗的抵抗。我们的研究小组一直在研究胰腺癌生长调节的机制，长期目标是设计早期诊断和治疗的策略。我们发现胰腺癌的生长在一定程度上是由胃肠激素和CCK通过一种独特的CCK受体调控的，该受体已被PI克隆和测序。由于该受体在胰腺癌组织中检测到，而在正常胰腺组织中检测不到，因此被称为“CCK-C”受体。初步研究表明，胰腺癌患者外周血中存在CCK-C受体RNA，而对照组的外周血中不存在CCK-C受体RNA。此外，一种针对癌症相关CCK-C受体的抗体通过Western分析、ELISA法和免疫组织化学实验识别人类癌细胞中的该受体。这项拨款假设CCK-C受体可能被用作胰腺癌早期检测的工具。为了验证这一假说，提出了以下具体目标：1)研究CCK-C受体在检测组织和血液中胰腺癌方面的特异性，使用一系列具有特定症状的G1门诊患者。2)应用RT-PCR和免疫细胞化学方法，对小鼠原位胰腺癌模型外周血及人血和胰液中CCK-C受体及其RNA的检测阶段进行了研究；3)用选择性受体抗体建立了人血浆CCK-C受体的ELISA检测方法。这些研究是申请人长期目标的一部分，目的是了解控制胰腺癌生长的机制，并在疾病的早期阶段对患者进行诊断，以提高长期存活率。

DESCRIPTION (provided by applicant): Pancreatic cancer is the 4th leading cause of cancer-related deaths in the United States and with the five- year survival rate of less than 1%, it remains the lowest of all malignancies. Reasons for the poor prognosis of pancreatic cancer include the inability to diagnose this malignancy in early stages and its resistance to standard chemotherapy. Our research group has been studying the mechanisms involving growth regulation of pancreatic cancer with the long-range goals of designing strategies for early diagnosis and treatment. We have found that growth of pancreatic cancer is in part regulated by the gastrointestinal peptides gastrin and CCK through a unique CCK receptor which has been cloned and sequenced by the PI. Since this receptor has been detected in cancerous pancreatic tissue and not in the normal pancreas, it has been called the "CCK-C" receptor. Preliminary studies show that the CCK-C receptor RNA is present in the peripheral blood of patients with pancreatic cancer but not in the blood from control subjects. Additionally, an antibody raised against the cancer-associated CCK-C receptor recognizes the receptor in human cancer cells by Western analysis, ELISA assay, and by immunohistochemical experiments. This grant hypothesizes that the CCK-C receptor may be utilized as a tool for the early detection of pancreatic cancer. In order to test this hypothesis, the following specific aims are proposed: 1) Study the specificity of the CCK-C receptor for the detection of pancreatic cancer in tissues and in blood using a case series of Gl outpatients with specific presenting symptoms. 2) Investigate the stage in which the CCK-C receptor or its RNA is detectable in the peripheral blood with both an orthotopic mouse pancreatic cancer model and with blood and pancreatic juices obtained from human subjects by RT-PCR and immunocytochemistry and 3) Develop an ELISA assay for the CCK-C receptor in human plasma with selective receptor antibodies. These studies are part of the applicant's long- term goals to understand the mechanisms controlling growth of pancreatic cancer and to diagnose patients in early stage of disease to improve long-term survival.