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Glycoprotein biomarkers for esophageal adenocarcinoma and barrett's esophagus and uses thereof

Inactive Publication Date: 2019-03-07
THE UNIV OF QUEENSLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new method for managing EAC and BE. It uses a biomarker to measure the level of at least one glycospecies. This method helps to determine the likelihood of presence or absence of EAC or BE. Overall, this technology improves the accuracy and effectiveness of managing EAC and BE.

Problems solved by technology

This is likely due to late stage diagnosis: approximately two thirds of patients who are diagnosed have advanced-stage disease, at which point current therapies are largely ineffective.
However, these endoscopic screening programs have limitations associated with sampling error, variability in assessment of biopsies between practitioners, and tissue heterogeneity.
Moreover, even with these endoscopic screening programs, more than 80% of EACs are diagnosed without any prior diagnosis of BE or gastroesophageal reflux disorder, more than 80% of patients with BE are undiagnosed (and thus not recommended for subsequent and ongoing screening programs), and many patients undergoing routine screening never progress to EAC.
This indicates that current screening methodologies are not particularly effective at identifying patients at high risk and distinguishing between those that progress to EAC and those that don't.

Method used

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  • Glycoprotein biomarkers for esophageal adenocarcinoma and barrett's esophagus and uses thereof
  • Glycoprotein biomarkers for esophageal adenocarcinoma and barrett's esophagus and uses thereof
  • Glycoprotein biomarkers for esophageal adenocarcinoma and barrett's esophagus and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Identification of Biomarkers for EAC

[0170]To identify biomarkers for EAC and BE, the abundance of proteins with altered glycosylation structures (i.e. different glycospecies) in the serum of healthy patients, patients with BE and patients with EAC was assessed using lectin-magnetic bead array-coupled mass spectrometry (LeMBA-MS) essentially as described by Choi et al. (Electrophoresis (2011) 32, 3564-3575). A schematic of the biomarker identification protocol is shown in FIG. 1.

Materials and Methods

Sample Preparation

[0171]In the discovery phase, 29 serum samples (TABLE 8), consisting of 10 each of BE, EAC and 9 healthy controls (4 confirmed BE-free from Study of Digestive Health and 6 population controls from Australian Cancer Study), were analysed. One of the control patients subsequently developed BE, so the data were excluded from further analysis. All of the patients were male, reflecting the male-dominance of EAC and BE.

[0172]The serum samples were denatured by heating in denat...

example 2

Detecting Combinations of Glycospecies

[0184]In order to determine whether a particularly robust set of markers could selected in order to improve the determination of the likelihood of the presence or absence of BE or EAC in a subject, combinations of glycospecies identified from the relevant table (TABLES 1, 4, and 6) were analysed.

[0185]It was found that the power of the diagnostic test could be enhanced by measuring a panel of two, three, four, five, or more than five markers (see, TABLE 11). Notably, when using four glycospecies (JAC-binding complement component C9, EPHA-binding alpha-1B-glycoprotein, EPHA-binding gelsolin, WGA-binding angiotensin and alpha-2-macroglobulin) are measured between subjects with EAC and healthy controls, an AUC of up to 98.25% can be achieved.

TABLE 11AUCGlycospecies (EAC v Healthy)P02748_JAC0.775P02748_JAC P04217_EPHA0.86P02748_JAC P04217_EPHA P06396_EPHA0.93P02748_JAC P04217_EPHA P06396_EPHA P01019_WGA0.9825P02748_JAC P04217_EPHA P06396_EPHA P01019...

example 3

Validation of Glycospecies Biomarkers

[0188]In order to demonstrate that glycospecies biomarkers can be reliably determine the likelihood of a subject having a relevant condition, a number of the biomarkers were selected for validation in a separate and distinct cohort of subjects.

[0189]TABLE 13 shows the relative increase or decrease of exemplary differentially glycosylated proteins in the serum of patients with EAC compared to healthy patients, BE compared to healthy patients, and in the serum of patients with EAC compared to patients with BE, i.e. the relative abundance of the specific glycospecies. For example, six proteins (P00738: haptoglobin, P00751: complement factor B, P01011: alpha-1-antichymotrypsin, P02748: complement component C9, P09871: complement Cls subcomponent, and P10643: complement component C7) having glycans that facilitated binding to EPHA (i.e. the EPHA-binding glycospecies of haptoglobin, the EPHA-binding glycospecies of complement factor B, the EPHA-binding...

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Abstract

Disclosed are biomarkers for Barrett's esophagus and esophageal adenocarcinoma, and uses thereof, such as in methods for detecting the presence, and monitoring progression, of Barrett's esophagus and esophageal adenocarcinoma. Also disclosed are methods for treating and methods of monitoring the treatment of Barrett's esophagus and esophageal adenocarcinoma, as well as kits and compositions for use in such methods.

Description

RELATED APPLICATIONS[0001]This application is the U.S. National Stage Application under 35 U.S.C. § 371 of International Application No. PCT / AU2015 / 050723, filed Nov. 17, 2015, designating the U.S. and published as WO 2016 / 077881 A1 on May 26, 2016, which claims priority to Australian Provisional Application No. 2014904616 entitled “Biomarkers and Uses Therefor”, filed on Nov. 17, 2014. Any and all applications for which a foreign or a domestic priority is claimed is / are identified in the Application Data Sheet filed herewith and is / are hereby incorporated by reference in their entirety under 37 C.F.R. § 1.57.FIELD OF THE INVENTION[0002]This invention relates generally to biomarkers for Barrett's esophagus and esophageal adenocarcinoma, and uses thereof, such as in methods for detecting the presence, and monitoring progression, of Barrett's esophagus and esophageal adenocarcinoma. The invention also relates to methods for treating and methods of monitoring the treatment of Barrett's...

Claims

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Application Information

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IPC IPC(8): G01N33/574G16H50/30G16H50/20
CPCG01N33/57469G01N33/57484G16H50/30G16H50/20Y02A90/10
Inventor HILL, MICHELLE MEI CHIHSHAH, ALOKCAO, KIM-AHN L
Owner THE UNIV OF QUEENSLAND
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