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，其五年生存率低于1%，仍然是所有恶性肿瘤中最低的。胰腺癌预后不良的原因包括无法在早期诊断这种恶性肿瘤及其对标准化疗的抵抗。我们的研究小组一直在研究涉及胰腺癌生长调节的机制，长期目标是设计早期诊断和治疗策略。我们已经发现胰腺癌的生长部分受胃肠道肽胃泌素和CCK通过一个独特的CCK受体调节，该受体已被PI克隆和测序。由于这种受体在癌性胰腺组织中检测到，而在正常胰腺中未检测到，因此被称为“CCK-C”受体。初步研究表明，胆囊收缩素C受体RNA存在于胰腺癌患者的外周血中，但不存在于对照受试者的血液中。此外，针对癌症相关CCK-C受体产生的抗体通过Western分析、ELISA测定和免疫组织化学实验识别人癌细胞中的受体。这项研究假设CCK-C受体可以作为胰腺癌早期检测的工具。为了检验这一假设，提出了以下具体目标：1）使用具有特定表现症状的GI门诊患者的病例系列研究CCK-C受体用于检测组织和血液中的胰腺癌的特异性。2)通过RT-PCR和免疫细胞化学研究在原位小鼠胰腺癌模型和从人类受试者获得的血液和胰液中检测到CCK-C受体或其RNA的阶段; 3）开发具有选择性受体抗体的人血浆中CCK-C受体的ELISA测定。这些研究是申请人的长期目标的一部分，以了解控制胰腺癌生长的机制，并在疾病的早期阶段诊断患者以改善长期生存。

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.