Targeted Glycomics and Affinity Reagents for Cancer Biomarker Development

用于癌症生物标志物开发的靶向糖组学和亲和试剂

• 批准号: 8351852
• 负责人: Brian B. Haab
• 金额: $ 55.49万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-08 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8351852
• 关键词: Address; Affinity; Antibodies; Antigens; Area; Benign; Binding; Biochemical; Bioinformatics; Biological; Biological Assay; Biological Markers; Biology; Blinded; CA-19-9 Antigen; Cancer Detection; Cancer Patient; Cancer Prognosis; Carcinoembryonic Antigen; Caring; Clinical; Computer software; Data; Detection; Development; Diagnosis; Diagnostic Procedure; Differential Diagnosis; Gene Expression; Genetic; Glycobiology; Goals; Individual; Lead; Lectin; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Measurement; Methods; Molecular Profiling; Monitor; Pancreas; Pancreatic Diseases; Patient Care; Patients; Pattern; Performance; Polysaccharides; Reagent; Research; Resources; Sampling; Screening procedure; Sensitivity and Specificity; Serum; Shotguns; Specificity; Staging; Structure; Subgroup; Testing; Time; Tn antigen; Training; Variant; Work; base; clinically relevant; glycosylation; high risk; improved; new technology; novel; novel diagnostics; overexpression; performance tests; research study; success; tool; tumor

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.

描述（申请人提供）：胰腺癌的新生物标志物在高危人群筛查、疑似癌症的准确诊断、预后和治疗预测、治疗过程中监测肿瘤进展等方面迫切需要。 CA 19-9 抗原是目前最好的胰腺癌标志物，但由于其在大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生物标志物，专门识别 CA 19-9 水平高或低且表现良好的患者 足以影响患者护理。研究表明，某些患者缺乏 CA 19-9 升高是由于糖基化机制的遗传或表达改变，而在表达 CA19-9 的患者中未发现这种改变。此外，我们还发现，某些 CA 19-9 水平较低的患者会产生替代聚糖，可用于特异性识别他们。我们的假设是 1) CA 19-9-low 和 CA 19-9-high 肿瘤是不同的生物实体，产生不同的聚糖结构； 2) CA 19-9-low 肿瘤特异性聚糖的检测与 CA 19-9 的检测结合使用形成了高度准确的生物标志物组。我们将使用以新的生物/生化信息为指导的强大的糖组学工具来检验这些假设。在目标 1 中，我们将开发新的亲和试剂并结合 Shotgun Glycomics 来识别和表征可以特异性检测 CA 19-9-low 肿瘤的聚糖。在目标 2 中，我们将从基因表达分析中获取生物学信息，以进一步指导聚糖的差异表达测试。在目标 3 中，确定的亲和试剂将用于生物标志物组的测试和开发。这些目标的完成将产生新的生物标志物来改善胰腺癌患者的护理，推进识别和开发基于聚糖的生物标志物的新策略，并为其他糖生物学项目提供新资源。 公共卫生相关性：胰腺癌患者诊断后的生存时间通常非常短。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。这项研究的目标是开发此类生物标志物。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。该领域的成功将导致开发这些或类似的标记物以满足其他需求，例如在高风险个体中进行筛查或为确诊癌症的患者选择最佳治疗方法。