INSULIN/IGF-1 PATHWAY IN BARRETT´S ESOPHAGUS
Chak Amitabh, Professor
Case Western Reserve Universitycity: Cleveland country: United States (us)
Grant 5R21CA135692-02 from National Cancer Institute
Abstract: 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
Keywords: Aberrant DNA Methylation; Address; Adenocarcinoma; Adenocarcinoma of the Esophagus; Adenoma, Malignant; adiposity; Advisory Committees; Affect; AKT; Akt protein; Animals; Antibodies; Apoptosis; Apoptosis Pathway; Arm; Assay; Autoregulation; Barrett Epithelium; Barrett Esophagus; Barrett Syndrome; Barrett Ulcer; base; Binding; Binding (Molecular Function); Binding Proteins; Bioassay; Biologic Assays; Biological Assay; biological signal transduction; biomarker; Biopsy; bowel; c-akt protein; Cancer Induction; Cancer of the Esophagus; Cancers; Candidate Disease Gene; Candidate Gene; Carbohydrates; carcinogenesis; case control; Case-Base Studies; Case-Comparison Studies; Case-Compeer Studies; Case-Control Studies; Case-Referent Studies; Case-Referrent Studies; Cell Communication and Signaling; Cell Death, Programmed; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cell Signaling; Cell Survival; Cell Transformation, Neoplastic; Cell Viability; Cellular Proliferation; Chemotherapy-Hormones/Steroids; Columnar Epithelial-Lined Lower Esophagus; Columnar-Lined Esophagus; Complex; corpulence; corpulency; corpulentia; Country; Coupled; Cross-Product Ratio; Development; Diet; Dietary Factors; Disease; disease/disorder; Disorder; Endocrine; Endocrine Gland Secretion; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Esophageal; Esophageal Adenocarcinoma; Esophageal Cancer; Esophageal Reflux; Esophagus Cancer; fasting glucose; Fats; Fatty acid glycerol esters; FK506 Binding Protein 12-Rapamycin Associated Protein 1; FK506 binding protein 12-rapamycin associated protein 1, human; FK506 Binding Protein 12-Rapamycin Associated Protein 2; FKBP-Rapamycin Associated Protein; FKBP-rapamycin associated protein, human; FKBP12 Rapamycin Complex Associated Protein 1; Forecast of outcome; FRAP1 protein, human; Frequencies (time pattern); Frequency; Future; Gastro-oesophageal Reflux; Gastroesophageal Reflux; Gastroesophageal reflux disease; Gene Inactivation; Gene Silencing; Generalized Growth; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; GERD; GFAC; Goals; Growth; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; heavy metal lead; heavy metal Pb; Homeostasis; Hormones; hTIMP; human FRAP1 protein; Human TIMP-3; Human Tissue Inhibitor of Metalloproteinase-3; Humulin R; Hyperinsulinemia; Hyperinsulinism; IBP3; IGF; IGF-1; IGF-1 Receptor; IGF-Binding Proteins; IGF-I; IGF-I-SmC; IGF1; IGF1R; IGFBP; IGFBP3; IGFBP3 gene; Immunochemistry; Incidence; indexing; Individual; Inflammation Mediators; INSR; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin Receptor; Insulin Receptor Protein-Tyrosine Kinase; Insulin Receptor Substrate 1; insulin receptor substrate 1 protein; Insulin Resistance; insulin resistant; Insulin, Regular; Insulin-Dependent Tyrosine Protein Kinase; Insulin-Like Growth Factor 1; Insulin-Like Growth Factor 1 Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factors; Insulin-Like Growth-Factor-Binding Proteins; Insulin-Like Somatomedin Peptide I; Insulin-Like-Growth Factor I Receptor; insulinlike growth factor; insulinlike growth factor binding protein; Intestinal; Intestinal Mucosa; Intestines; Intracellular Communication and Signaling; IRS-1 protein; IRS1; L-Tyrosine; Lead; Ligand Binding Protein; Link; malignancy; Malignant Esophageal Neoplasm; Malignant Esophageal Tumor; Malignant neoplasm of esophagus; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Esophagus; Measures; Mediator; Mediator of Activation; Mediator of activation protein; Metaplastic; Methods; Methylation; Modeling; Molecular; Molecular Interaction; mTOR; Mucosa; Mucosal Tissue; Mucous Membrane; Mutation; National Institutes of Health; National Institutes of Health (U.S.); neoplasia; neoplasm/cancer; Neoplasms; neoplastic; Neoplastic Cell Transformation; neoplastic growth; neoplastic transformation; NIH; Novolin R; obese; obese people; obese person; obese population; Obesity; Obesity associated cancer; Obesity related cancer; Odds Ratio; Oncogenesis; ontogeny; outcome forecast; pandemic; pandemic disease; para-Tyrosine; paracrine; pathway; Pathway interactions; Patients; Pb element; Physiological Homeostasis; Pilot Projects; pilot study; PKB protein; Pressure; pressure; Pressure- physical agent; Process; Prognosis; Protein Kinase B; Protein Methylation; protein-serine-threonine kinase (rac); proto-oncogene protein akt; proto-oncogene protein RAC; Proto-Oncogene Proteins c-akt; Public Health; public health medicine (field); rac protein kinase; RAC-PK protein; RAFT1 protein, human; rapamycin and FKBP12 target 1 protein, human; Rapamycin Target Protein; RAPT1 protein, human; Receptor, IGF Type 1; Receptor, IGF-I; Receptor, Insulin-Like Growth Factor Type 1; Reflux; Regulation; related to A and C-protein; Relative Odds; Research; Risk; Risk Factors; Risk Ratio; Role; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; social role; Somatomedin C; Somatomedin-Binding Proteins; Somatomedins; Squamous Epithelium; Stratification; Sulfation Factor; Surrogate Markers; Task Forces; Therapeutic Agents; Therapeutic Hormone; TIMP-3; Tissue Growth; Tissue Inhibitor of Metalloproteinase-3; translation research enterprise; Translational Research; Translational Research Enterprise; Translational Science; tumor; Tumor Tissue; tumorigenesis; Tumors; TYR; Tyrosine; Tyrosine Phosphorylation; Tyrosine, L-isomer; United States; United States National Institutes of Health; Upper arm; Visceral
Project start date: 2008-07-21
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
PFA/PA: PA-06-413
5R21CA135692-02 (2009): $224775
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Chak Amitabh
Chak Amitabh, Professor
Case Western Reserve Universitycity: Cleveland country: United States (us)
Grant 3R01DK070863-05S1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Barrett´s esophagus is the precursor of esophageal adenocarcinoma. Both Barrett´s esophagus and esophageal adenocarcinoma are closely associated with gastroesophageal reflux. Screening endoscopy is therefore recommended for the evaluation of chronic gastroesophageal reflux symptoms. Endoscopic surveillance, performed in those identified with Barrett´s esophagus, detects cancer at an early stage. However, the large majority of these cancers occur in previously undiagnosed Barrett´s esophagus and nearly half of these persons have no history of gastroesophageal reflux symptoms. Identification of genetic risk factors would lead to more effective screening programs and improved understanding of the molecular pathogenesis of these diseases. Our prior case control study demonstrated familial aggregation of Barrett´s esophagus and its associated cancers, which we termed Familial Barrett´s Esophagus. We have since developed family recruitment and endoscopic screening methods to identify Familial Barrett´s Esophagus. Recent molecular genetic studies have identified one putative locus and suggest the existence of at least one other locus linked to these diseases. These family recruitment, endoscopic screening, and genetic analysis methods will now be used to test the following central hypothesis Familial Barrett Esophagus has a genetic basis. The specific aims of this proposal are (1) To recruit and screen family members of esophageal adenocarcinoma patients, comparing age of cancer onset between probands classified as familial with those classified as apparently sporadic; (2) To perform endoscopic screening and measure the recurrence risk of Barrett´s esophagus in siblings of probands with Barrett´s esophagus and esophageal adenocarcinoma; and (3) To identify loci and map susceptibility genes associated with Familial Barrett´s Esophagus. Using the multidisciplinary approach of our collaborative team of investigators, these aims will result in new information regarding a genetic predisposition to the development of Barrett´s esophagus and esophageal adenocarcinoma
Keywords: Affect; Age; Barrett Esophagus; base; cancer diagnosis; Candidate Disease Gene; Case-Control Studies; Caucasoid Race; Chronic; Complex; Data; data mining; design; Development; Diagnosis; Disease; Endoscopy; Enrollment; Esophageal Adenocarcinoma; Esophagogastric Junction; Esophagoscopy; Evaluation; Familial disease; Family; Family history of; Family member; First Degree Relative; Gastroesophageal reflux disease; Genes; Genetic; genetic analysis; genetic linkage; genetic pedigree; Genetic Predisposition to Disease; genetic risk factor; Genome Scan; Germ Lines; Germ-Line Mutation; Hospitals; improved; Incidence; indexing; Individual; Inherited; interdisciplinary approach; Interdisciplinary Study; Lead; Link; male; Malignant neoplasm of esophagus; Malignant Neoplasms; Maps; Measures; member; Metaplasia; Methods; Molecular; Molecular Genetics; Mutate; Newly Diagnosed; Odds Ratio; Onset of illness; Pathogenesis; Patients; Persons; physical mapping; Predisposition; proband; programs; Questionnaires; Recording of previous events; Recruitment Activity; Recurrence; Reporting; Research Personnel; Research Project Grants; research study; Risk; Risk Factors; Screening procedure; sex; Siblings; Somatic Mutation; Staging; Surveillance Program; Susceptibility Gene; Symptoms; Testing; Tissue Banking; Tissue Banks; trait; virtual
Project start date: 2005-09-30
Project end date: 2012-08-31
Budget start date: 26-SEP-2011
Budget end date: 31-AUG-2012
3R01DK070863-05S1 (2011): $387664
5R01DK070863-05 (2009): $777874