DCLK1 as a Marker/Indicator of Stem Cell Response in Barrett's Esophagus/Esophageal Adenocarcinoma

March 4, 2020 updated by: University of Oklahoma

Doublecortin Like Kinase-1 as a Marker and Indicator of Treatment Response for Intestinal Stem Cells in Barrett's Esophagus and Progression to Esophageal Adenocarcinoma

The hypotheses are: 1) the intestinal stem cell marker, DCLK1, which is increased in both the epithelium and stroma in colon cancer is also increased in BE (Barrett's esophagus) with HGD (high grade dysplasia) and in EAC (esophageal adenocarcinoma), 2) this expression correlates with disease progression towards EAC and 3) eradication of cells expressing stem cell markers occurs after therapy of EMR (endoscopic mucosal resection) or RFA (radiofrequency ablation) to eradicate BE with HGD and intramucosal adenocarcinoma and esophagectomy for EAC. We will test our hypotheses with the following aims: 1) To characterize the cell specific expression patterns of intestinal stem cell biomarkers in BE patients and correlate them with serum expression and disease progression, 2) To examine prospectively the effects of EMR, RFA or esophagectomy on the expression of stem cell biomarkers and the progression to EAC.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Barrett's esophagus (BE) is a metaplasia of normal squamous epithelium. BE can progressively develop more abnormal features like low-grade intraepithelial dysplasia (LGID), high-grade intraepithelial dysplasia (HGID) before ultimately developing esophageal adenocarcinoma (EAC), with a low 5-year survival rate of 20 % or less. Recent evidence for the existence of cancer stem cells (CSCs) has advanced our understanding of cancer and has opened doors to new therapeutic strategies in cancer treatment. The fundamental goals of this project are to determine the effectiveness of endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) on eradication of putative intestinal stem cell markers that are overexpressed in BE with HGID and EAC. A better understanding of the cellular mechanisms that regulate the progression from normal squamous mucosa to EAC has enormous implications in the diagnosis and treatment of esophageal cancer. The presence of a CSC in esophageal cancer has been reported in both dysplastic BE/ EAC as well as in mouse models of the disease. The central hypotheses of the current proposal are: elimination of cells expressing stem cell markers occurs after ablative therapies (EMR/RFA) to eradicate BE with HGID/ EAC, and monitoring of stem cell marker expression during follow-up will correlate with disease recurrence or appropriate clinical response. Recently, we have reported that DCLK1, although minimally expressed in normal distal esophageal squamous mucosa, is markedly expressed in BE epithelium and EAC. We will test our central hypotheses with the following specific aims: 1. To prospectively characterize the cell specific expression patterns of putative intestinal stem cell biomarkers in BE patients and correlate them with serum/plasma protein expression and disease progression, 2. to examine prospectively the effects of EMR/RFA on the expression of putative stem cell biomarkers and correlate them with serum/plasma protein expression and disease progression and/or recurrence, and 3. to examine prospectively the effects on EMR/ RFA on esophageal-related quality of life and dysphagia during the endoscopic intervention period as well as following completion. The studies proposed have the potential to offer new insights for both the early diagnosis and monitoring of therapeutic response of future therapies for EAC. Moreover, these studies may identify novel biomarkers that can aid in the confirmation of HGID and potentially predict disease onset, progression and/or recurrence. Finally, these studies have the potential to provide preliminary data that will serve as the rationale for large scale multicenter trials to compare the effectiveness of EMR and RFA in BE with respect to clinical outcome, molecular features and effect on putative tumor stem cells. The recent identification of DCLK1 as a marker that distinguishes between normal and tumor stem cells in a rodent model of intestinal tumorigenesis lends support for our rationale for examining DCLK1 as a potential mediator of the neoplastic response in BE.

Study Type

Observational

Enrollment (Actual)

32

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Gastroenterology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients presenting for upper endoscopy to evaluate symptoms or risk factors such as GERD, dyspepsia, or dysphagia with a finding of BE or EAC; treatment with EMR or RFA for BE with HGD, focal intramucosal adenocarcinoma or esophagectomy for EAC.

Description

Inclusion Criteria:

  • BE length of 12 cm or less
  • presence of non-dysplastic BE on 2 sequential endoscopies or low-grade intraepithelial dysplasia (LGIN), high-grade intraepithelial dysplasia (HGIN) or EAC in BE segment on 2 endoscopies in the previous 6 months
  • no signs of metastasis on endoscopic ultrasonography or computerized tomography scan.

Exclusion Criteria:

  • pre-RFA EMR with cancer at the resection margin
  • greater than T1sm1 invasion
  • poor differentiation or worse
  • angiolymphatic invasion
  • esophageal stenosis preventing passage of an 11.3 mm endoscope
  • persistent visible lesions after EMR before RFA and invasive cancer on biopsies after EMR pre-RFA.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Other
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
DCLK1 post BE treatment
Effects of EMR and RFA on the expression of putative stem cell biomarkers and correlate them with serum/plasma protein expression and disease progression and/or recurrence (Barrett's esophagus/ esophageal adenocarcinoma)
Other: EMR and RFA effect on stem cell marker expression in BE/EAC
Observation of EMR and RFA on the expression of putative stem cell biomarkers and correlate them with serum/plasma protein expression and disease progression and/or recurrence (Barrett's esophagus/ esophageal adenocarcinoma)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
cell-specific expression patterns of putative intestinal stem cell biomarkers in BE patients; correlation of markers with serum/plasma protein expression and disease progression.
Time Frame: 2 yrs
Exploratory; analysis of expression of various markers for Barrett's esophagus and esophogeal adenocarcinoma
2 yrs

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oklahoma

Investigators

  • Principal Investigator: Ahmed Bolkhir, MD, University of Oklahoma

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2013

Primary Completion (Actual)

August 13, 2019

Study Completion (Actual)

August 13, 2019

Study Registration Dates

First Submitted

September 26, 2013

First Submitted That Met QC Criteria

May 3, 2018

First Posted (Actual)

May 16, 2018

Study Record Updates

Last Update Posted (Actual)

March 6, 2020

Last Update Submitted That Met QC Criteria

March 4, 2020

Last Verified

March 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1885

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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