Carbohydrate Antigenic Biomarkers for Epithelial Cancers

上皮癌的碳水化​​合物抗原生物标志物

• 批准号: 8352005
• 负责人: MINORU FUKUDA
• 金额: $ 51.65万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-04 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8352005
• 关键词: Adhesions; Adopted; Anabolism; Antibodies; Antigens; Autoantibodies; Autoimmune hemolytic anemia; Benign; Biological Assay; Biological Markers; Biopsy; Breast; Breast Cancer Cell; Cancer Patient; Carbohydrate Sequence; Carbohydrates; Cell surface; Cells; Cellular Structures; Cellular biology; Chronic; Clinical; Computational Biology; Coupled; Detection; Diagnosis; Diagnostic; Disease; Enzymes; Epithelial; Epithelial Cells; Evaluation; Glycolipids; Glycoproteins; Human; Human Herpesvirus 4; Immune; Immunobiology; Individual; Infection; Intervention; Lead; Link; Lymphoid Tissue; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Membrane Glycoproteins; Methods; Microarray Analysis; Monoclonal Antibodies; Mucins; Mycoplasma pneumoniae; Neoplasms; PC3 cell line; Patients; Pattern; Polysaccharides; Procedures; Prognostic Marker; Proteins; Proteomics; Reporting; Research; Role; Scientist; Screening procedure; Serum; Small Interfering RNA; Specificity; Specimen; Structure; System; Technical Expertise; Technology; Testing; Tissues; Transfection; Tumor Biology; Tumor-Associated Carbohydrate Antigens; Vertebral column; base; cancer cell; carbohydrate structure; cell type; design; effective therapy; glycosyltransferase; immunogenic; improved; malignant breast neoplasm; meetings; novel; oncology; outcome forecast; poly-N-acetyllactosamine; prognostic; success; sulfotransferase; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The major focus of the proposed project is the characterization and subsequent application of potential biomarkers of prevalent epithelial cancers in humans: the prostate cancer-specific carbohydrate antigen, F77, and for breast cancer, the more broadly-expressed epithelial cancer-associated carbohydrate antigen, AE3, both recognized by monoclonal antibodies. The project brings together a team of scientists with hugely complementary expertise and technical capabilities in carbohydrates, immunobiology, cancer cell biology, oncology, proteomics, and computational biology, as well as unique and well-annotated clinical specimens. We intend to adopt two main approaches to the structural characterization of F77 and AE3 antigens. The first is carbohydrate microarray analysis coupled with mass spectrometry using glycan arrays generated from the prostate cancer cell line, PC-3, and from AE3 antigen-positive epithelial mucins. The second is cell transfection of specific glycosyltransferases and other glyco-modifying enzymes such as sulfotransferases, an approach that has recently met with considerable success. Once characterized, the F77 and AE3 antigenic glycan sequences will be included as key probes in a carbohydrate microarray platform that we have established that presently includes more than 700 glycan sequences of glycoproteins and glycolipids. This will open the way to analysis of cancer patient sera for the presence of autoantibodies to F77 and AE3 and any other glycan biomarkers and to the design of new analysis procedures for the detection of aberrant glyco-antigenemia; one such approach will be by immune-proteomics. The expression of F77 and AE3 antigens will also be evaluated as tissue-based prognostic markers to identify aggressive primary prostate cancer. Finally, the mechanistic role of the F77 antigen in metastatic capabilities of cancer cells will be investigated to link the presence of the biomarker to the biology of the tumor. For prostate and breast cancers, existing screening methods for detection and characterization are variously unsatisfactory and unreliable. The application of biomarkers to detect prostate and breast cancer and to provide information about the prognosis of individual patients would be extremely useful and provide a very desirable alternatives to the current low sensitivity and/or specificity screening methods. PUBLIC HEALTH RELEVANCE: This research aims to develop novel tissue- or serum-based biomarkers for breast and prostate cancer based on cancer-specific carbohydrate antigens. Characterization of the antigens will lead to antibody- or antigen-directed assays that can improve diagnosis and/or prognosis for these common cancers. This will improve screening strategies to better distinguish benign from malignant disease and decrease unnecessary biopsies or other interventions, and inform treatment decisions to diminish over-therapy of non-aggressive disease and enable earlier and more effective therapy of aggressive disease.

描述（由申请人提供）：拟议项目的主要重点是人类常见上皮癌潜在生物标志物的表征和后续应用：前列腺癌特异性碳水化合物抗原 F77，以及乳腺癌中表达更广泛的碳水化合物抗原上皮癌相关碳水化合物抗原 AE3，均能被单克隆抗体识别。该项目汇集了一支科学家团队，他们在碳水化合物、免疫生物学、癌细胞生物学、肿瘤学、蛋白质组学和计算生物学以及独特且注释充分的临床标本方面具有巨大互补的专业知识和技术能力。我们打算采用两种主要方法来表征 F77 和 AE3 抗原的结构。第一个是碳水化合物微阵列分析与质谱分析相结合，使用从前列腺癌细胞系 PC-3 和 AE3 抗原阳性上皮粘蛋白产生的聚糖阵列。第二种是特定糖基转移酶和其他糖修饰酶（例如磺基转移酶）的细胞转染，这种方法最近取得了相当大的成功。一旦确定特征，F77 和 AE3 抗原聚糖序列将作为关键探针纳入我们已建立的碳水化合物微阵列平台中，该平台目前包括 700 多个糖蛋白和糖脂的聚糖序列。这将为分析癌症患者血清中是否存在针对 F77 和 AE3 以及任何其他聚糖生物标志物的自身抗体以及设计用于检测异常糖抗原血症的新分析程序开辟道路；其中一种方法是免疫蛋白质组学。 F77 和 AE3 抗原的表达也将作为基于组织的预后标志物进行评估，以识别侵袭性原发性前列腺癌。最后，将研究F77抗原在癌细胞转移能力中的机制作用 将生物标志物的存在与肿瘤的生物学联系起来。对于前列腺癌和乳腺癌，现有的检测和表征筛查方法都不尽如人意且不可靠。应用生物标志物检测前列腺癌和乳腺癌并提供有关个体患者预后的信息将非常有用，并且为当前的低灵敏度和/或特异性筛查方法提供了非常理想的替代方案。 公共健康相关性：本研究旨在开发基于癌症特异性碳水化合物抗原的新型基于组织或血清的乳腺癌和前列腺癌生物标志物。抗原的表征将导致抗体或抗原导向的测定，可以改善这些常见癌症的诊断和/或预后。这将改进筛查策略，以更好地区分良性和恶性疾病，减少不必要的活检或其他干预措施，并为治疗决策提供信息，以减少对非侵袭性疾病的过度治疗，并能够更早、更有效地治疗侵袭性疾病。