Early Cancer Detection & Prognosis through Glycomics

描述(申请人提供)：我们不是寻找特定的癌症生物标记物(蛋白质或糖基化蛋白质)，而是强调在未分离的生物样本中进行定量去糖基化(去除糖链)，并在定量糖链图谱中显示去除的糖链。比较来自健康和疾病个体的血糖谱应该可以确定与癌症相关的结构变化。另一方面，预后或对患者健康的差异性评估则依赖于对这种糖链模式的同位素辅助定量MS测量。在我们拟议研究的前两个阶段，临床相关的样本将通过我们完善的程序进行筛选，同时使用最先进的基于MS的方法和毛细管电泳法。在第一阶段，从健康女性和男性收集的人类血清的血糖模式将与从卵巢癌、前列腺癌、肺癌和结肠癌患者收集的血清进行比较。通过生物信息学和统计评估，将确定与每种类型的癌症或与所有要研究的癌症类型相关的葡聚糖标记物的清单。这对于确定糖基化或“糖基化异常”的发生的定量趋势，并将这些测量与确定的糖链结构联系起来是必要的。CE-LIF为相同样本获取的血糖谱将有助于确定由于结构异构体的变化而导致的变化，而这些变化不能通过MS确定。在第二阶段，将比较癌症患者血清在特定药物治疗前后的血糖图谱。在这一阶段，将密切监测第一阶段中定义的一组多糖的变化，并将评估它们因癌症进展或缓解而产生的变化。第二阶段的结果将证实或否定在第一阶段将被定义为潜在生物标记物的潜在的糖链结构。一旦确定了这些特定的糖链变化或由于疾病进展或缓解而改变的一组糖链结构，将研究更快的筛选方法的可能性，如凝集素或抗体微阵列。这就是本研究第三阶段的目的，该阶段将侧重于确定可用作诊断和预后工具的最佳分析工具。

DESCRIPTION (provided by applicant): Rather than looking for specific cancer biomarkers (proteins or glycosylated proteins), we emphasize quantitative deglycosylation (removal of glycans) in unfractionated biological samples and displaying the removed glycans in quantitative glycan maps. Comparing glycomic profiles originating from healthy and diseased individuals should allow the assignment of structural changes associated with cancer. On the other hand, prognosis or a differential assessment of patients' health then relies on the isotopically-aided quantitative MS measurements of such glycan patterns. In the first two phases of our proposed research, clinically relevant samples will be screened through our well-established procedures while using the state-of- the-art MS-based methodologies and capillary electrophoresis. In Phase 1, the glycomic patterns of human blood serum collected from healthy females and males will be compared to those collected from ovarian, prostate, lung and colon cancer patients. Through bioinformatic and statistical evaluation a list of glycan markers that are associated with each type of cancer or with all types of cancer to be studied will be determined. This is necessary to establish quantitative trends in glycosylation or the occurrence of "glycosylation aberrations" and link these measurements to positively identified glycan structures. Glycomic profiles acquired for the same samples by CE-LIF will aid in determining changes that are due to changes in structural isomers which cannot be determined through MS. In Phase 2, the glycomic maps of human blood serum of cancer before and after treatment with a specific drug will be compared. In this phase, changes in the set of glycans defined in Phase 1 will be closely monitored and their changes as a result of cancer progression or remission will be evaluated. Phase 2 results will confirm or refute the potential glycan structures that will be defined as potential biomarkers in Phase 1. Upon the identification of these specific glycan changes or the set of glycan structures that change as a result of disease progression or remission, the potential of a faster screening approach such as lectin or antibody microarrays will be investigated. This is the aim of Phase 3 of this study which will focus on defining the best analytical tools that could be utilized as diagnostic and prognostic tool.