Defining Secreted Glycan Alterations in Pancreatic Cancer

描述（由申请人提供）：开发准确检测早期胰腺癌并更好区分良性和恶性疾病的方法可以大大改善胰腺癌患者的结局。已知胰腺上皮细胞的恶性转化导致由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。糖基化蛋白形成了目前用于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蛋白质，然后孵育聚糖结合蛋白（如凝集素）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，与癌症特别相关，无论是在改变的表达模式和改变的蛋白质上的聚糖结构。在R21阶段，我们将确定这些蛋白质类别成员上的多种特异性聚糖的水平，以检验以下假设：与仅测量蛋白质或仅测量聚糖水平相反，测量特定蛋白质上的特定癌症相关聚糖将提高癌症检测的灵敏度和特异性。该项目的R33阶段将扩展并彻底测试该方法。将在来自患有胰腺癌、良性胰腺疾病、其他癌症和无疾病的受试者的大量血清样品中表征使用粘蛋白、CEA蛋白和R33期鉴定的蛋白上的聚糖的测量来检测胰腺癌的灵敏度和特异性。我们期望表征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一般性和频率。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。这项研究可能会导致显着改善血液测试检测癌症，以及一个强大的，普遍适用的平台，研究碳水化合物改变对多种蛋白质。

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.