Glycoproteins and Glycan-Binding IgGs: Biomarkers for Cancer and Inflammatory Di
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 orcell 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 levelsometimes 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 prostatecancer 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 theglycan 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 plasmasamples. 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. PUBLIC HEALTH RELEVANCE: Due to increased life expectancy in the US, the percentage of the population suffering from chronic inflammatory diseases and cancers will increase each year. Cancer biomarkers sometimes fail to distinguish early stage cancer from benign or inflammatory diseases. Prostate cancer is the most common malignancy in American men. Currently, the measurement of serum PSA is used for cancer diagnosis but specificity of the PSA assay is not satisfactory. Approximately 75% of biopsy samples of individuals with PSA levels between 4 and 10 ng/ml were tumor negative. Thus, we propose to search oligosaccharide-related prostatecancer biomarkers for early prostate cancer diagnosis to compensate for shortcomings in specificity of the PSA test. New concepts and technologies developed for the prostate cancer diagnostics can be utilized for detection of other cancers and inflammatory diseases.
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