Defining Secreted Glycan Alterations in Pancreatic Cancer

描述(申请人提供)：开发准确检测早期胰腺癌并更好地区分良恶性疾病的方法可以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会导致这些细胞分泌或释放的某些蛋白质的碳水化合物链发生变化。糖化蛋白构成了目前用于检测胰腺癌和其他腺癌的生物标记物的基础，预计这些检测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糖链，并识别与胰腺癌相关的特定糖链结构。该方法使用抗体微阵列从血清样本中捕获特定蛋白，然后孵育糖结合蛋白(如凝集素)以定量捕获蛋白上的特定多糖。粘蛋白和癌胚抗原相关蛋白这两类糖蛋白与癌症尤其相关，它们的表达模式和蛋白上的糖链结构都发生了变化。在R21阶段，我们将确定这些蛋白质类别成员上的多个特定糖链的水平，以测试这样一个假设，即测量特定蛋白质上的特定癌症相关糖链，而不是只测量蛋白质或只测量多糖水平，将产生更高的癌症检测灵敏度和特异性。该项目的R33阶段将扩展并彻底测试该方法。通过测量粘蛋白、CEA蛋白和R33期蛋白上的糖链来检测胰腺癌的敏感性和特异性将在大量来自胰腺癌、良性胰腺疾病、其他癌症和无疾病的受试者的血清样本中得到表征。我们期望确定这些测量对于疾病诊断的价值，并获得对分泌蛋白上特定糖链改变的普遍性和频率的洞察。与公共卫生相关：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进用于检测癌症的血液测试，并为研究多种蛋白质上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.