Defining Secreted Glycan Alterations in Pancreatic Cancer

描述（申请人提供）：胰腺癌早期准确检测和良恶性鉴别方法的发展，将极大地改善胰腺癌患者的预后。众所周知，胰腺上皮细胞的恶性转化导致这些细胞分泌或释放的某些蛋白质的碳水化合物链的改变。糖基化蛋白构成了目前检测胰腺癌和其他腺癌的生物标志物的基础，并且预测这些测试的改进将能够检测早期胰腺癌。我们的初步数据表明，一种新的抗体微阵列技术可以有效地检测不同蛋白质上的聚糖，并识别与胰腺癌相关的特定聚糖结构。该方法使用抗体微阵列从血清样品中捕获特定的蛋白质，然后将聚糖结合蛋白（如凝集素）孵育以定量捕获蛋白质上的特定聚糖。两类糖蛋白，粘蛋白和癌胚抗原相关蛋白，通过改变表达模式和改变蛋白上的聚糖结构与癌症密切相关。在R21阶段，我们将确定这些蛋白质类别成员上的多个特定聚糖的水平，以测试特定蛋白质上特定癌症相关聚糖的测量，而不是仅测量蛋白质或仅测量聚糖水平的假设，将提高癌症检测的敏感性和特异性。该项目的R33阶段将扩展并彻底测试该方法。通过测量粘蛋白、CEA蛋白和R33期鉴定的蛋白上的聚糖来检测胰腺癌的敏感性和特异性，将在来自胰腺癌、良性胰腺疾病、其他癌症和无疾病受试者的大量血清样本中进行表征。我们期望描述这些测量对疾病诊断的价值，并深入了解分泌蛋白上特定聚糖改变的普遍性和频率。与公共卫生的相关性：在早期阶段更准确地诊断癌症的能力可能会改善许多患者的预后。这项研究可能会显著改善用于检测癌症的血液测试，并为研究多种蛋白质的碳水化合物变化提供一个强大的、普遍适用的平台。

DESCRIPTION (provided by applicant): The development of methods to accurately detect early pancreatic cancer and to better differentiate benign from malignant disease could greatly improve the outcomes for pancreatic cancer patients. It is known that malignant transformation of epithelial cells of the pancreas results in alterations in the carbohydrate chains of certain proteins secreted or released by these cells. Glycosylated proteins form the basis for current biomarkers for detecting pancreatic cancer and other adenocarcinomas, and refinement of these tests are predicted to enable detection of early pancreatic cancer. Our preliminary data has shown that a novel antibody-microarray technology allows the efficient detection of glycans on distinct proteins and the identification of specific glycan structures associated with pancreatic cancer. The method uses antibody microarrays to capture specific proteins from serum samples, followed by the incubation of a glycan-binding protein (such as a lectin) to quantify specific glycans on the captured proteins. Two classes of glycoproteins, mucins and carcinoembryonic-antigen-related proteins, are particularly associated with cancer, both in altered expression patterns and in altered glycan structures on the proteins. In the R21 phase, we will determine the levels of multiple specific glycans on members of those protein classes to test the hypothesis that the measurement of specific cancer-associated glycans on specific proteins, as opposed to measuring just protein or just glycan levels, will yield improved sensitivities and specificities for cancer detection. The R33 phase of the project will expand and thoroughly test the approach. The sensitivity and specificity of detecting pancreatic cancer using measurements of glycans on mucins, CEA proteins, and proteins identified in the R33 phase will be characterized in a large set of serum samples from subjects with pancreatic cancer, benign pancreatic disease, other cancers, and no disease. We expect to characterize the value of these measurements for disease diagnostics and to gain insights into the generality and frequency of specific glycan alterations on secreted proteins. Relevance to public health: The ability to more accurately diagnose cancers at earlier stages could lead to improved outcomes for many patients. This research could lead to significantly improved blood tests for the detection of cancer, as well as a powerful, generally- applicable platform for studying carbohydrate alterations on multiple proteins.