Validation of potential early diagnostic and prognostic markers for pancreatic ca

胰腺癌潜在早期诊断和预后标志物的验证

• 批准号: 7091767
• 负责人: PAUL J CHIAO
• 金额: $ 11.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-06 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091767
• 关键词: clinical research; early diagnosis; neoplasm /cancer; pancreas neoplasms

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is the fourth most common cause of cancer death in the developed world. Less than 10% of patients survive for more than 1 year following diagnosis and the 5-year survival rate (1-3%) is the lowest of any cancer. Despite the advance in the research of pancreatic cancer, patients with this devastating disease have a very poor prognosis. Current chemotherapy, radiation therapy, and surgical procedures are largely ineffective in the treatment of this disease because most pancreatic cancers have already progressed into locally advanced unresectable or metastatic disease at the time of diagnosis. The goal of this proposal is to identify markers for detecting pancreatic cancer at an early stage by using a simple non-invasive screening test. When pancreatic cancer has not reached to advance, unresectable or metastatic stages, survival of patients with pancreatic cancer can be improved by using therapeutic approaches such as pancreaticoduodenectomy plus chemoradiation. The most promising approach for the early diagnosis of cancer utilizes tumor markers. However, tumor marker with both high sensitivity and high specificity, especially for screening and diagnosis of early stages of pancreatic cancer remains to be found. By using different approaches for screening differentially expressed genes between the normal and pancreatic tumor and between nonmetastatic and metastatic pancreatic tumor cell lines, overexpression of gamma synuclein and tropomyosin-related kinase B (TrkB) was identified. High levels of gamma synuclein can be found by immunoblotting in 38% (21 of 56) of blood samples from pancreatic cancer patients, but not in normal controls. Overexpression of TrkB was found in metastatic human pancreatic cancer cells and correlated with liver metastasis in pancreatic cancer patients. In the proposed study, we will determine whether gamma synuclein is a potential tumor marker for early detection of pancreatic cancer by developing more sensitive assays such as ELISA for analyzing blood samples from normal controls and patients with pancreatic cancer and other type of cancers as well as sera from benign diseases such as pancreatitis and hepatitis. We will examine the expression of y-synuclein in PanlN stages. We will determine whether TrkB is a potential prognostic marker for pancreatic cancer metastasis by correlating the levels of TrkB immunostaings from surgical specimens and endoscopic retrograde cholangiopancreatography (ERCP) samples with the various stages of pancreatic cancer. Our proposed experimental approaches represent the required verification step in identification of tumor marker for diagnosis and prognosis regardless of the techniques used in the initial screening. Our study may identify the tumor markers for developing an early detection method for screening of asymptomatic cases to detect pancreatic cancer at an early, localized, and curable stage. Our results may also provide a prognostic marker for metastasis of pancreatic cancer and a direction for the rational treatment of patients with pancreatic cancer, and the future clinical studies required to extend the survival of these patients.

描述（由申请人提供）：胰腺腺癌是发达国家癌症死亡的第四大原因。诊断后，不到10％的患者生存超过1年，而5年生存率（1-3％）是任何癌症中最低的。尽管胰腺癌的研究有所进步，但这种毁灭性疾病的患者的预后较差。当前的化学疗法，放射治疗和外科手术在这种疾病的治疗中基本上是无效的，因为在诊断时，大多数胰腺癌已经发展为局部晚期无法切除或转移性疾病。该提案的目的是通过使用简单的非侵入性筛查测试来鉴定在早期阶段检测胰腺癌的标记。当胰腺癌尚未达到前进，不可切除或转移性阶段时，胰腺癌患者的存活可以通过使用胰腺十二指肠切除术以及化学疗法等治疗方法来改善。早期诊断癌症的最有希望的方法利用了肿瘤标记。然而，具有高灵敏度和高特异性的肿瘤标记，尤其是在筛查和诊断胰腺癌早期阶段的肿瘤标记尚待发现。通过使用不同的方法在正常和胰腺肿瘤之间以及非转移性和转移性胰腺肿瘤细胞系之间筛选差异表达的基因，鉴定了γ-突触核蛋白和tropomyosin相关激酶B（TRKB）的过表达。通过在胰腺癌患者的38％（56个）的血液样本中进行免疫印迹，可以发现高水平的伽马核素，但在正常对照组中却找不到。在转移性人胰腺癌细胞中发现了TRKB的过表达，并与胰腺癌患者的肝转移相关。在拟议的研究中，我们将通过开发更敏感的测定法（例如ELISA），例如分析正常对照组的血液样本和胰腺癌患者以及其他类型的癌症以及诸如胰腺炎和胰腺炎的良性疾病的血液样本来确定γ-突触核蛋白是否是早期检测胰腺癌的潜在肿瘤标志物。我们将检查panln阶段中Y-突触核蛋白的表达。我们将通过将手术标本中的TRKB免疫抑制剂和内镜逆行胆管造影术（ERCP）样品与胰腺癌的各个阶段相关联，确定TRKB是否是胰腺癌转移的潜在预后标记。我们提出的实验方法代表了识别肿瘤标记物进行诊断和预后的所需验证步骤，无论初始筛查中使用的技术如何。我们的研究可能会确定用于开发早期检测方法的肿瘤标志物，以筛查无症状病例以在早期，局部和可治愈的阶段检测胰腺癌。我们的结果还可能为胰腺癌转移和胰腺癌患者合理治疗的方向提供预后标记，以及扩展这些患者存活所需的未来临床研究。