Targeted Glycomics and Affinity Reagents for Cancer Biomarker Development

描述(申请人提供)：在几个方面迫切需要新的胰腺癌生物标志物：在高危人群中进行筛查，对疑似癌症的准确诊断，预后和治疗预测，以及在治疗过程中监测肿瘤的进展。CA19-9抗原是目前诊断胰腺癌的最佳标记物，但由于其在很大一部分患者中缺乏表达，其应用受到限制。这项研究的目标是开发一组胰腺癌的生物标记物，专门识别CA19-9水平高或低且表现良好的患者 足以影响病人护理。研究表明，某些患者缺乏CA19-9升高是由于糖基化机制中的基因或表达改变，在表达CA19-9的患者中没有发现。此外，我们已经证明，某些CA19-9水平低的患者会产生替代的多糖，可以用来专门识别他们。我们的假设是：1)CA19-9-Low和CA19-9-High肿瘤是产生不同糖链结构的不同生物实体；2)CA19-9-Low肿瘤特异性糖链的检测与CA19-9的检测相结合，形成了一个高精度的生物标志物小组。我们将在新的生物/生化信息的指导下，使用强大的糖组学工具来验证这些假说。在目标1中，我们将利用新型亲和试剂的开发与鸟枪式糖胺化合物相结合来鉴定和表征可能特异性检测CA19-9-Low肿瘤的多糖。在目标2中，我们将从基因表达分析中获得生物信息，以进一步指导糖链差异表达的测试。在目标3中，鉴定的亲和试剂将用于生物标志物面板的测试和开发。这些目标的完成将产生新的生物标记物，以改善对胰腺癌患者的护理，推进识别和开发基于糖链的生物标记物的新战略，并为其他糖生物学项目提供新的资源。

DESCRIPTION (provided by applicant): New biomarkers for pancreatic cancer are urgently needed on several fronts: screening among high-risk individuals, accurate diagnosis of suspected cancer, prognosis and treatment prediction, and monitoring the progress of tumors during the course of treatment. The CA 19-9 antigen is the best current marker for pancreatic cancer, yet its use is limited owing to its lack of expression in a significant fraction of patient. The goal of this research is to develop a panel of biomarkers for pancreatic cancer that specifically identifies patients that are either high or low in CA 19-9 and that would perform well enough to impact patient care. Research has shown that the lack of CA 19-9 elevation in certain patients is due to genetic or expression alterations in the glycosylation machinery not found in CA19-9-expressing patients. In addition, we have shown that certain patients who are low in CA 19-9 produce alternative glycans that can be used to specifically identify them. Our hypotheses are 1) the CA 19-9-low and CA 19-9-high tumors are distinct biological entities that produce divergent glycan structures; and 2) the detection of the glycans specific to CA 19-9-low tumors used in combination with the detection of CA 19-9 forms a highly accurate biomarker panel. We will use powerful glycomics tools guided by new biological/biochemical information to test these hypotheses. In Aim 1, we will use the development of new affinity reagents combined with Shotgun Glycomics to identify and characterize glycans that may specifically detect CA 19-9-low tumors. In Aim 2, we will derive biological information from gene expression analysis to further guide the testing of glycans for differential expression. In Aim 3, the identified affinity reagent will be used in the testing and development of biomarker panels. The completion of these aims will result in new biomarkers to improve the care of pancreatic cancer patients, the advancement of a new strategy for identifying and developing glycan-based biomarkers, and new resources for other glycobiology projects.