Targeted Glycomics and Affinity Reagents for Cancer Biomarker Development

描述（由申请人提供）：在几个方面迫切需要胰腺癌的新生物标志物：高风险个体中的筛查，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。CA 19-9抗原是目前胰腺癌的最佳标志物，但由于其在相当一部分患者中缺乏表达，其使用受到限制。这项研究的目标是开发一组胰腺癌的生物标志物，专门识别CA 19-9高或低的患者，并且表现良好 足以影响病人的护理。研究表明，在某些患者中缺乏CA 19-9升高是由于在表达CA 19 -9的患者中未发现的糖基化机制中的遗传或表达改变。此外，我们已经证明，某些CA 19-9低的患者产生可用于特异性识别它们的替代聚糖。我们的假设是1）CA 19-9-低和CA 19-9-高肿瘤是产生不同聚糖结构的不同生物实体;和2）与CA 19-9的检测组合使用的对CA 19-9-低肿瘤特异性的聚糖的检测形成高度准确的生物标志物组。我们将使用新的生物/生化信息指导的强大的糖组学工具来测试这些假设。在目标1中，我们将使用与Shotgun Glycomics相结合的新亲和试剂的开发来鉴定和表征可以特异性检测CA 19-9低肿瘤的聚糖。在目标2中，我们将从基因表达分析中获得生物学信息，以进一步指导聚糖差异表达的检测。在目标3中，确定的亲和试剂将用于生物标志物组的检测和开发。这些目标的完成将产生新的生物标志物，以改善胰腺癌患者的护理，促进识别和开发基于聚糖的生物标志物的新策略，以及其他糖生物学项目的新资源。 公共卫生相关性：胰腺癌患者在诊断后的生存时间通常很短。更好地识别胰腺癌并指导治疗决策的新诊断方法可以使这些患者受益匪浅。这项研究的目的是开发这样的生物标志物。该项目产生的生物标志物的最初预期用途是提高疑似癌症患者早期诊断的准确性。这一领域的成功将导致这些或类似标记物的开发，以满足其他需求，例如在高风险个体中进行筛查或为确诊癌症患者选择最佳疗法。

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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer patients typically have very short survival times after diagnosis. New diagnostic methods to better identify pancreatic cancer and guide treatment decisions could greatly benefit these patients. The goal of this research is to develop such biomarkers. The initial intended use of the biomarkers resulting from this project is to improve the accuracy of early-stage diagnosis among patients with suspected cancer. Success in that area would lead to the development of these or similar markers for other needs, such as screening among high-risk individuals or selecting the best therapy for patients with confirmed cancer.