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

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大原因，其5年生存率低于1%，是所有恶性肿瘤中最低的。胰腺癌预后差的原因包括早期无法诊断和对标准化疗的耐药。我们的研究小组一直在研究胰腺癌的生长调节机制，并为早期诊断和治疗设计策略。我们发现胰腺癌的生长在一定程度上是由胃肠道肽胃泌素和CCK通过一个独特的CCK受体调节的，该受体已被PI克隆和测序。由于这种受体在癌变胰腺组织中被检测到，而在正常胰腺中没有被检测到，因此它被称为“CCK-C”受体。初步研究表明，CCK-C受体RNA存在于胰腺癌患者的外周血中，而不存在于对照组的血液中。此外，一种针对癌症相关CCK-C受体的抗体通过Western分析、ELISA测定和免疫组织化学实验识别人类癌细胞中的受体。该基金假设CCK-C受体可能被用作胰腺癌早期检测的工具。为了验证这一假设，提出以下具体目的：1)通过具有特定表现症状的Gl门诊患者病例系列，研究CCK-C受体在组织和血液中检测胰腺癌的特异性。2)采用RT-PCR和免疫细胞化学方法，在原位小鼠胰腺癌模型和人血液和胰液中检测外周血中CCK-C受体或其RNA的阶段；3)采用选择性受体抗体，建立人血浆中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，旨在了解控制胰腺癌生长的机制，并在疾病早期诊断患者以提高长期生存率。

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.