Glycoproteins and Glycan-Binding IgGs: Biomarkers for Cancer and Inflammatory Di

糖蛋白和聚糖结合 IgG：癌症和炎症性疾病的生物标志物

• 批准号: 8535687
• 负责人: Hyesook Kim
• 金额: $ 14.09万
• 依托单位: DETROIT R & D, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535687
• 关键词: Affinity; Affinity Chromatography; Age; American; Anabolism; Antibodies; Autoantibodies; Autoimmune Process; Benign; Benign Prostatic Hypertrophy; Binding; Binding Proteins; Bioinformatics; Biological; Biological Assay; Biological Markers; Biopsy Specimen; Biotinylation; Blood; Cancer Diagnostics; Cell Adhesion; Chronic; Clinical; Data; Detection; Development; Diagnostic Neoplasm Staging; Digoxigenin; Disease; Dyes; Enzyme-Linked Immunosorbent Assay; Fractionation; Genetic Polymorphism; Glycoproteins; Hodgkin Disease; Housing; Hydrophobicity; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Individual; Inflammation; Inflammatory; Investigation; Keyhole Limpet Hemocyanin; Label; Lead; Lectin; Length; Life Expectancy; Liquid substance; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Methodology; Molecular Profiling; Monitor; Monoclonal Antibodies; Mus; Noise; Oligosaccharides; Pathway interactions; Patients; Phase; Physiological; Plasma; Polysaccharides; Population; Principal Component Analysis; Printing; Production; Prostate Cancer Vaccine; Prostate specific antigen measurement; Prostate-Specific Antigen; Race; Relative (related person); Research; Sample Size; Sampling; Serum; Shapes; Signal Transduction; Signaling Protein; Slide; Solutions; Specificity; Spottings; Staging; Structure; System; Technology; Testing; Therapeutic; Tissues; Tumor Tissue; Wit; antigen binding; base; biological systems; cancer diagnosis; cancer risk; data mining; flexibility; glycoprotein structure; high throughput technology; malignant breast neoplasm; men; phase 1 study; prostatitis; protein aminoacid sequence; screening; statistics; therapeutic vaccine; tool; tumor; tumor progression; vaccine candidate; vaccine development; vector

DESCRIPTION (provided by applicant): Structurally varied glycans displayed unexpectedly strong efects on inflammation and cancer progression. Glycan recognition by glycan-binding proteins is involved with physiological and disease-related cell adhesion or cell signaling. Tumor tissues secrete glycoproteins, which induce autoantibody production. Glycoprotein glycan levels and structures in cancer differ from those found in benign or inflammatory diseases. Recently, a few cancer-specific glycan biomarkers were identified by screening microarrayed glycans with immunoglobulin (Ig) fractions isolated from breast cancer and classical Hodgkin's lymphoma (cHL) patients. For both studies, subsequent direct ELISAs with larger sample sizes verified the glycan biomarkers. These studies demonstrated that glycans recognized by Igs are disease-specific and reliable biomarkers. Increased prostate-specific antigen (PSA) coreprotein levels have been widely used to detect, stage and monitor prostate cancer. However, PSA level sometimes cannot distinguish cancer from benign or inflammatory diseases. In a recent study, ~20 out of 250 plasma samples from cancer-free individuals had PSA levels higher than 4 ng/ml (false PSA positives) probably due to BPH or prostatitis. Moreover, ~75% of biopsy samples of individuals with PSA levels between 4 - 10 ng/ml were tumor negative. Thus, we propose to identify prostate cancer biomarkers to compensate for shortcomings in specificity of the PSA test. Combination of high-throughput technologies (glycoprotein and glycan microarrays) and fractionation technologies dependent on glycan structures and glycan-binding specificity of the IgG or IgM (2 major Igs involved with cancer) show promise of obtaining molecular signatures to distinguish prostate cancer from BPH. During Phase I, we will (a) identify prostate cancer-specific plasma glycoprotein (coreprotein and glycan) biomarkers by lectin/antibody microarray analyses with 26 glycoprotein biomarker candidates, e.g., glycosylated PSA, (b) develop prostate cancer-specific 70 glycan microarrays using glycan linkers selected among 9 in-house synthesized linkers of various lengths and hydrophobicity and (c) detect glycan-binding profiles of IgGs or IgMs to obtain prostate cancer-specific biomakers by the glycan microarray. Single or signature prostate cancer biomarkers of glycoprotein or glycan Ig pair will be identified using Statistics and Bioinformatics tools. Specificity of the biomarkers will be further investigated wit the false PSA positive plasma samples. During Phase II, clinical direct ELISAs and glycan subarrays for extensive plasma and tissue screening will be produced based on the Phase I study. Increased prostate cancer risk and aggressiveness will be studied in relation to oligosacharide biosynthesis pathway polymorphisms. New concepts and technologies developed during Phases I and II can be applied for general searches of biomarkers for other cancers or inflammatory diseases with various biological fluids and tissues. Identification of prostate cancer- specific glycans recognized by autoantibodies will lead to development of glycan-based therapeutics.

描述（由申请人提供）：结构不同的聚糖对炎症和癌症进展表现出意想不到的强烈影响。聚糖结合蛋白的聚糖识别涉及生理和疾病相关的细胞粘附或细胞信号传导。肿瘤组织分泌糖蛋白，诱导自身抗体的产生。癌症中的糖蛋白聚糖水平和结构与良性或炎症性疾病中的糖蛋白聚糖水平和结构不同。最近，通过使用从乳腺癌和经典霍奇金淋巴瘤 (cHL) 患者中分离的免疫球蛋白 (Ig) 片段筛选微阵列聚糖，鉴定出了一些癌症特异性聚糖生物标志物。对于这两项研究，随后使用更大样本量的直接 ELISA 验证了聚糖生物标志物。这些研究表明，Igs 识别的聚糖是疾病特异性且可靠的生物标志物。前列腺特异性抗原（PSA）核心蛋白水平的升高已被广泛用于检测、分期和监测前列腺癌。然而，PSA 水平有时无法区分癌症与良性或炎症性疾病。在最近的一项研究中，来自无癌症个体的 250 个血浆样本中约有 20 个的 PSA 水平高于 4 ng/ml（PSA 假阳性），可能是由于 BPH 或前列腺炎。此外，PSA 水平在 4 - 10 ng/ml 之间的个体的活检样本中，约 75% 的肿瘤呈阴性。因此，我们建议鉴定前列腺癌生物标志物以弥补 PSA 测试特异性的缺陷。高通量技术（糖蛋白和聚糖微阵列）和依赖于 IgG 或 IgM（与癌症有关的两种主要 Ig）的聚糖结构和聚糖结合特异性的分级技术相结合，有望获得区分前列腺癌和 BPH 的分子特征。在第一阶段，我们将 (a) 通过凝集素/抗体微阵列分析 26 种糖蛋白生物标志物候选物（例如糖基化 PSA）来鉴定前列腺癌特异性血浆糖蛋白（核心蛋白和聚糖）生物标志物，(b) 使用从 9 个内部选择的聚糖接头开发前列腺癌特异性 70 种聚糖微阵列 合成不同长度和疏水性的接头，(c) 检测 IgG 或 IgM 的聚糖结合谱，通过聚糖微阵列获得前列腺癌特异性生物标志物。将使用统计和生物信息学工具来鉴定糖蛋白或聚糖 Ig 对的单一或特征性前列腺癌生物标志物。将使用假 PSA 阳性血浆样本进一步研究生物标志物的特异性。在第二阶段，将基于第一阶段研究生产用于广泛血浆和组织筛查的临床直接 ELISA 和聚糖子阵列。将研究与寡糖生物合成途径多态性相关的前列腺癌风险和侵袭性增加。第一阶段和第二阶段开发的新概念和技术可应用于各种生物体液和组织的其他癌症或炎症性疾病的生物标志物的一般搜索。自身抗体识别的前列腺癌特异性聚糖的鉴定将导致基于聚糖的疗法的开发。

项目成果

Levels of plasma glycan-binding auto-IgG biomarkers improve the accuracy of prostate cancer diagnosis.

• DOI: 10.1007/s11010-020-03876-7
• 发表时间: 2021-01
• 期刊: Molecular and cellular biochemistry
• 影响因子: 4.3
• 作者: Dos Santos JM;Joiakim A;Kaplan DJ;Putt DA;Perez Bakovic G;Servoss SL;Rybicki BA;Dombkowski AA;Kim H
• 通讯作者: Kim H