Grant Number:	1R21CA135692-01A1 Interpret this number
Primary Investigator:	Chak, Amitabh
Organization:	Case Western Reserve University
Project Title:	Insulin/Igf-1 Pathway in Barrett's Esophagus
Fiscal Year:	2008

DESCRIPTION (provided by applicant): The alarming rise in esophageal adenocarcinoma incidence over the past 3 decades coupled with a poor prognosis make this cancer an important national public health issue. Adenocarcinoma of the esophagus arises in Barrett's esophagus, a pre- neoplastic metaplastic transformation of the squamous epithelium that is closely associated with gastroesophageal reflux. We, and others, have found that Barrett's esophagus and esophageal adenocarcinoma are independently linked to obesity. The increased incidence of these diseases is partially attributable to a pandemic of obesity in this country. Increased levels of insulin and the Type 1 insulin growth factor are postulated to be a key mechanistic link between obesity, the Western diet, and carcinogenesis in other cancers. Our central hypothesis is that "hyperinsulinemia and high levels of Type 1 insulin growth factor (IGF-1) possibly related to the Western diet in susceptible individuals contribute to genetic and epigenetic changes in the esophageal epithelium that are key to the development of Barrett's esophagus and its subsequent progression to esophageal adenocarcinoma". Components of this complex hypothesis will be explored in this case control study whose aims are -- to 1. Calculate insulin resistance and measure free IGF-1; 2. Assay phosphorylated insulin receptor substrate- 1 (phos-IRS-1) immunostaining; and 3. Assess for aberrant methylation of selected candidate genes in Barrett's esophagus patients and control subjects. Successful conduct of this pilot study will enable future studies which are: a) examining the interaction of the insulin/IGF proliferative pathway with gastreoesophageal reflux in esophageal carcinogenesis; b) studies to identify important dietary factors in the development of Barrett's esophagus; c) risk stratification of Barrett's esophagus based on biomarkers; and d) trials of potential therapeutic agents based on the insulin/IGF pathway. The research proposed in this application will determine whether increased level of the hormones, insulin and insulin growth factor-1, explain the link between obesity and adenocarcinoma of the esophagus. It will also enable studies to identify factors in the Western diet that might predispose to the development of Barrett's esophagus and cancer. Furthermore, this research will identify biomarkers that may lead to methods for identifying people with Barrett's esophagus who are at risk for developing cancer and lead to treatments aimed at halting or reversing this process.




Inverse Association Between Gluteofemoral Obesity and Risk of Barrett's Esophagus in a Pooled Analysis.
Authors: Kendall B.J. , Rubenstein J.H. , Cook M.B. , Vaughan T.L. , Anderson L.A. , Murray L.J. , Shaheen N.J. , Corley D.A. , Chandar A.K. , Li L. , et al. .
Source: Clinical Gastroenterology And Hepatology : The Official Clinical Practice Journal Of The American Gastroenterological Association, 2016 Oct; 14(10), p. 1412-1419.e3.
PMID: 27264393
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Associations of Serum Adiponectin and Leptin With Barrett's Esophagus.
Authors: Greer K.B. , Falk G.W. , Bednarchik B. , Li L. , Chak A. .
Source: Clinical Gastroenterology And Hepatology : The Official Clinical Practice Journal Of The American Gastroenterological Association, 2015 Dec; 13(13), p. 2265-72.
PMID: 25737442
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Association of insulin and insulin-like growth factors with Barrett's oesophagus.
Authors: Greer K.B. , Thompson C.L. , Brenner L. , Bednarchik B. , Dawson D. , Willis J. , Grady W.M. , Falk G.W. , Cooper G.S. , Li L. , et al. .
Source: Gut, 2012 May; 61(5), p. 665-72.
PMID: 21930730
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The microRNAs, MiR-31 and MiR-375, as candidate markers in Barrett's esophageal carcinogenesis.
Authors: Leidner R.S. , Ravi L. , Leahy P. , Chen Y. , Bednarchik B. , Streppel M. , Canto M. , Wang J.S. , Maitra A. , Willis J. , et al. .
Source: Genes, Chromosomes & Cancer, 2012 May; 51(5), p. 473-9.
PMID: 22302717
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Aberrantly methylated PKP1 in the progression of Barrett's esophagus to esophageal adenocarcinoma.
Authors: Kaz A.M. , Luo Y. , Dzieciatkowski S. , Chak A. , Willis J.E. , Upton M.P. , Leidner R.S. , Grady W.M. .
Source: Genes, Chromosomes & Cancer, 2012 Apr; 51(4), p. 384-93.
PMID: 22170739
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DNA methylation profiling in Barrett's esophagus and esophageal adenocarcinoma reveals unique methylation signatures and molecular subclasses.
Authors: Kaz A.M. , Wong C.J. , Luo Y. , Virgin J.B. , Washington M.K. , Willis J.E. , Leidner R.S. , Chak A. , Grady W.M. .
Source: Epigenetics, 2011 Dec; 6(12), p. 1403-12.
PMID: 22139570
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