Novel approaches to study immune responses to post translational modifications for cancer detection

研究癌症检测翻译后修饰免疫反应的新方法

基本信息

批准号：
9767078
负责人：
Karen Sue Anderson
金额：
$ 43.97万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-21 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767078
关键词：
Antibodies Antibody Response Autoantibodies B-Lymphocytes Biochemical Markers Biological Markers Biometry Biopsy Blinded Bos taurus structural-GP protein Breast Breast Cancer Early Detection CLIA certified Cancer Control Cancer Detection Cancer Patient Cells Data Detection Development Devices Diagnosis Disease Early Detection Research Network Early Diagnosis Enzyme-Linked Immunosorbent Assay Epitopes Extracellular Domain GALNT3 gene Glycoproteins Goals Human Human Papillomavirus Image Imaging technology Immune Immune Sera Immune response Immunity In Situ Laboratories Length Malignant Neoplasms Malignant neoplasm of lung Mammography Measures Medical Oncology Membrane Proteins Methods Molecular Chaperones Morbidity - disease rate Mucins Ovarian Patients Performance Phase Polysaccharides Post-Translational Protein Processing Predictive Value Production Protein Glycosylation Proteins Proteome Proteomics Protocols documentation Recombinants Reproducibility Research Design Ribosomes Screening for cancer Screening procedure Sensitivity and Specificity Serum Serum Immunologic Structure Suggestion Surface Technology Testing Training Translating Tumor Antigens Validation base biomarker development biomarker discovery biomarker identification cancer biomarkers chest computed tomography clinical biomarkers cost design early detection biomarkers gene cloning glycoprotein structure glycoproteomics glycosylation glycosyltransferase immunogenic improved improved outcome malignant breast neoplasm mortality novel novel strategies overexpression polypeptide potential biomarker prevent programs protein expression quality assurance rapid detection rapid technique screening seal sugar sugar nucleotide synthetic peptide tool triple-negative invasive breast carcinoma tumor validation studies

项目摘要

Project Summary/Abstract Despite advances in screening and treatment, mortalities from breast and lung cancers have remained high in the US over the last 20 years. It is widely accepted that early detection is critical to improving outcomes in both diseases. Both also rely on imaging for screening, but false positive and false negative detection are associated with unnecessary biopsies, missed diagnoses, and costs. There is an urgent need for biochemical markers that improve the performance of imaging technologies. Our laboratories have been successful at identifying useful cancer biomarkers by exploiting patients’ own ability to produce antibodies against tumor- associated antigens (TAA), referred to as tumor-associated autoantibodies (TAAb). With prior EDRN support, we developed high-throughput programmable protein display methods for the rapid detection and validation of autoantibody biomarker signatures in breast and lung cancers. Our breast cancer TAAb biomarkers have been licensed and integrated into Videssa™ Breast that is now available as CLIA-certified test. Our triple negative breast cancer markers have been validated in blinded phase 2 multicenter validation studies. These demonstrate the great utility of TAAb in cancer early detection. However, the sensitivities of most TAAbs is moderate and there is a suggestion that greater sensitivity and specificity could be obtained by examining TAAb directed at aberrantly modified proteins in cancers. Our central hypothesis is that aberrant protein glycosylation, a hallmark of breast and lung cancers, induces glycoprotein-specific TAAb that can be measured as specific serum biomarkers of these cancers. Alterations in glycosylation are highly immunogenic, and there is strong historical evidence for significant antibody responses to cancer-altered glycoproteins. However, all current protein (or polypeptide) display tools allow limited or no post-translational modification. This historical roadblock has prevented the identification of these biomarkers because of the lack of screening methods that test immunogenic structural glycoproteins. We introduce a tool for the high-throughput display of full-length proteins decorated with cancer-specific O-glycan structures. This will revolutionize the opportunity to screen glycan-protein epitopes in their natural context. Our team comprises strong expertise in functional proteomics, biomarker development, glycoproteomics, medical oncology and biostatistics. Targeted proteins will include: the extra-cellular domains of relevant single pass membrane proteins, proteins known to be O-glycosylated and overexpressed in the two cancers, and all known mucins. They will be translated in situ using human ribosomes and chaperone proteins and then systematically decorated with Tn and STn O-GalNAc-type glycans by consecutive addition of recombinant glycosyltransferases and sugar nucleotides to mirror what occurs in the two cancers. Adhering to the principles of PRoBE design, we will screen these arrays with cancer patient and control sera. Our study will focus on cancer patients and non-cancer subjects with positive imaging findings. Study design will include Phase I discovery (arrays/ELISA) and Phase II validation using ELISA.

项目摘要/摘要尽管在筛查和信任方面取得了进步，但乳房和肺罐头的死亡率在过去的20年中疾病。与不必要的活检，遗漏的诊断和成本相关。改善成像技术的标记。通过爆炸性患者自己生产抗体抗体的能力来确定有用的癌症生物标志物相关抗原（TAA），称为肿瘤相关的自身抗体（TAAB）。我们开发了高通量可编程蛋白，以显示快速检测和验证的方法乳腺癌和肺癌中的自身抗体特征是我们的乳腺癌。已被许可并集成到Videssa™乳房THAST中，现在可以作为我们的三重负面测试乳腺癌在盲期的2期多中心验证研究中得到了验证。证明了Taab在癌症早期检测中的巨大效用。中等，有一个建议，即通过检查可以获得更大的敏感性和特异性 TAAB针对癌症异常修饰的蛋白质。糖基化是乳腺癌和肺癌的标志，可诱导糖蛋白特异性Taab Taav 作为癌症的特定血清生物标志物。是对改变癌症糖蛋白的大量抗体反应的强大历史证据。当前的蛋白质（或多肽）展示工具允许有限或无需翻译后修饰。障碍已经阻止了生物标志物的识别，因为缺乏那些人的sckods 测试免疫原性糖蛋白。用癌症特定的O-聚糖结构装饰的蛋白质。在自然背景下，聚糖 - 蛋白质表现。生物标志物开发，糖蛋白质组学，医学肿瘤学和生物统计学将包括：相关的单个通过膜蛋白的细胞外结构域，已知为O-糖基化的蛋白并在两个癌症中过度陈述，所有已知的粘液都将使用人类的原位翻译核糖体和伴侣蛋白以及thype，然后系统地用Tn O-galnac型聚糖装饰通过奉献重组糖糖糖和糖核苷酸的奉献，以反映发生在两个癌症。控制血清。研究设计将包括使用ELISA的I发现（阵列/ELISA）和II期验证。