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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：
10463894
负责人：
Karen Sue Anderson
金额：
$ 18.32万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10463894
关键词：
Antibodies Antibody Response Autoantibodies B-Lymphocytes Biochemical Markers Biological Markers Biometry Biopsy Blinded 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 Structure Suggestion Surface Technology Testing Training Translating Tumor Antigens Validation base biomarker development biomarker discovery biomarker identification biomarker signature cancer biomarkers chest computed tomography clinical biomarkers cost design early detection biomarkers gene cloning 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 structural glycoprotein 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.

项目总结/文摘

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Programmable protein arrays for immunoprofiling HPV-associated cancers.

DOI：
10.1002/pmic.201500376
发表时间：
2016-04
期刊：
Proteomics
影响因子：
3.4
作者：
Ewaisha R;Meshay I;Resnik J;Katchman BA;Anderson KS
通讯作者：
Anderson KS

Serum autoantibodyome reveals that healthy individuals share common autoantibodies.

DOI：
10.1016/j.celrep.2022.110873
发表时间：
2022-05-31
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Shome, Mahasish;Chung, Yunro;Chavan, Ramani;Park, Jin G.;Qiu, Ji;LaBaer, Joshua
通讯作者：
LaBaer, Joshua

Proteomic Monitoring of B Cell Immunity.

B 细胞免疫的蛋白质组学监测。