DCLK1 as a Marker/Indicator of Stem Cell Response in Barrett's Esophagus/Esophageal Adenocarcinoma
Condition: Barrett's Esophagus; Esophageal Adenocarcinoma
MeSH terms: Adenocarcinoma; Barrett Esophagus; Esophageal Neoplasms
Study type: Observational

Summary: 
      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.
    

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.
    

Intervention name(s): EMR and RFA effect on stem cell marker expression in BE/EAC
Intervention type(s): Other
Intervention description(s): 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)
Observational model: Other
Time perspective: Prospective
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.
      
Keywords: DCLK1; Serum Biomarker; Barrett's Esophagus; Esophageal Adenocarcinoma; Tumor Stem Cell Marker