Affinity Based Strategies to Fast Track Development of Colon Cancer Biomarkers

基于亲和力的策略快速开发结肠癌生物标志物

• 批准号: 8284426
• 负责人: SAMIR M HANASH
• 金额: $ 61.08万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-16 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284426
• 关键词: Affinity; Antibodies; Apoptosis; Biological Markers; Cancer Etiology; Cessation of life; Colon; Colon Carcinoma; Colorectal Cancer; Custom; Development; Diagnosis; Diagnostic; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Goals; Incubated; Inflammation; Insulin Resistance; Lectin; MAP Kinase Gene; Malignant Neoplasms; Methods; Pathway interactions; Phospho-Specific Antibodies; Plasma; Process; Prostaglandins; Proteins; Proteome; Proteomics; Regulation; Sampling; Screening procedure; Signal Pathway; Sorting - Cell Movement; Specificity; Technology; Tissue Sample; Tissues; Toll-like receptors; Transforming Growth Factors; Triage; United States; Validation; angiogenesis; base; density; glycosylation; improved; novel; tumor

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is one of the most common cancers in the United States and the second ranked cause of cancer related death. This project proposes to perform both broad proteomic and glycomic screens and targeted analyses to discover early detection and diagnostic biomarkers of CRC. The goal is to improve colon screening by the addition of highly sensitive markers that together with each other or existing markers yield good specificity. We will interrogate unique prediagnostic plasma samples, tissue from primary CRC tumors, and plasma from CRC cases on custom high-density antibody microarrays (up to 6000 different analytes) to discover novel proteomic and glycomic biomarkers. Parallel arrays will be incubated with plasma or tissue lysate for proteomic comparison or glycosylation (via incubation with different lectins). This microarray approach employs technology with unparalleled sensitivity, enabling interrogation down to the low picomolar concentration of the circulating proteome. Biomarker candidates that pass the statistical threshold on a "discovery" array will be retained and be re-examined using new samples on smaller arrays (to reduce the false discovery rate) - a step we will refer to as "pre-validation" to indicate that a potential biomarker would have shown up as statistically significant in multiple sample sets but was not yet subjected to formal characterization or validation. This unique triage process allows for rapid sorting of potential biomarkers, allowing us to focus on only the most promising. The best candidates will then be evaluated with more conventional ELISA and lectin based methods. Our approaches will specifically target proteomic and glycomic changes in proteins critical for the regulation of apoptosis, proliferation, angiogenesis, inflammation/prostaglandins, insulin resistance, toll-like receptor (TLR), transforming growth factor (TGF)-¿ and STAT signaling pathway deregulation during CRC to discover biomarkers of early detection and diagnosis. These include over 300 phospho-specific antibodies and their matched non-phospho-specific counterparts to 21 MAPK, 12 TGF-¿, and many STAT pathway targets.

描述（由申请人提供）：结直肠癌 (CRC) 是美国最常见的癌症之一，也是癌症相关死亡的第二大原因。该项目建议进行广泛的蛋白质组学和糖组学筛查以及针对性分析，以早期发现癌症。 CRC 的检测和诊断生物标志物的目标是通过添加高度敏感的标志物来改进结肠筛查，这些标志物与彼此或现有的标志物一起产生良好的特异性。定制高密度抗体微阵列（多达 6000 种不同的分析物）上的 CRC 病例血浆，以发现新的蛋白质组和糖组生物标志物。平行阵列将与血浆或组织裂解液一起孵育，以进行蛋白质组比较或糖基化（通过与不同的凝集素一起孵育）。这种微阵列方法采用了具有无与伦比的灵敏度的技术，能够对循环蛋白质组的低皮摩尔浓度进行询问。在“发现”阵列上通过统计阈值的生物标志物候选物将被保留，并使用较小阵列上的新样本重新检查（以减少错误发现率）——我们将这一步骤称为“预验证”以表明潜在的生物标志物在多个样本集中显示出统计显着性，但尚未经过正式的表征或验证。这种独特的分类过程可以对潜在的生物标志物进行快速分类，使我们能够只关注最有前途的生物标志物。然后将对候选人进行评估我们的方法将专门针对对细胞凋亡、增殖、血管生成、炎症/前列腺素、胰岛素抵抗、Toll 样受体 (TLR)、转化生长因子 (TGF) 调节至关重要的蛋白质的蛋白质组和糖组变化。 ) )-¿ CRC 期间 STAT 信号通路失调，以发现早期检测和诊断的生物标志物，其中包括 300 多种磷酸特异性抗体及其与 21 MAPK、12 TGF-¿ ，以及许多 STAT 通路靶标。