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Principal Investigator: Timothy Cragin Wang
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2020
Award: $162,000
Funding agency: National Cancer Institute
PROJECT SUMMARY
The SARS-CoV-2 pandemic has led to massive morbidity and mortality worldwide due to COVID-19, with the
United States particularly affected. Risk factors for COVID-19 include male sex, older age, and obesity,
amongst others, which are also key risk factors for Barrett’s esophagus (BE) and esophageal adenocarcinoma
(EAC). Thus, patients with BE will likely be infected with SARS-CoV-2 at markedly higher rates compared to
the general population. Thus, patients with BE will likely be infected with SARS-CoV-2 at markedly higher rates
compared to the general population. SARS-CoV-2 infects cells by binding to the angiotensin-converting
enzyme 2 (ACE2) receptor and subsequent viral spike protein cleaving by transmembrane serine protease 2
(TMPRSS2). Infection induces key pathways and downstream effectors, resulting in pronounced inflammation.
ACE2 is highly expressed in esophageal tissue, ACE inhibitors reduce NF-κB protein expression in BE, and
ACE inhibitor use is associated with reduced risk of EAC. It is therefore plausible that SARS-CoV-2 infection in
BE patients can result in direct effects on BE tissues that accelerate neoplasia. We published a retrospective
cohort study of >1,600 hospitalized COVID-19 patients and found that use of the histamine-2 receptor
antagonist famotidine was associated with a >2-fold reduction in the risk of death. While potential mechanisms
underlying this observation remain poorly understood, famotidine may not only improve short-term clinical
outcomes in these patients but also ameliorate the pro-neoplastic effects of SARS-CoV-2 in BE. Proton pump
inhibitors (PPIs) were associated with worse outcomes in the cohort study, and we previously showed that PPI
administration leads to increases in the renin-angiotensin pathway in the gut microbiome. Thus, we
hypothesize the following: 1) BE patients with a history of COVID-19 are at increased risk for progression to
EAC; and 2) famotidine may be indicated instead of PPIs for BE patients with a documented history of COVID-
19. In this proposal we will address the following specific aims: Aim 1) To define the functional role of ACE2
and TMPRSS2 in BE and EAC cells; Aim 2) To determine whether famotidine influences SARS-CoV-2
infection in BE and EAC cells; Aim 3) To assess the relationship between TMPRSS2 and ACE2 expression
and immune cell populations in BE. A history of COVID-19 may represent a novel marker for risk for
progression to EAC among BE patients, and this may need to be incorporated into clinical profiles aimed at
identifying appropriate high-risk patients for screening and surveillance. Furthermore, treatment with famotidine
and not PPIs may be more appropriate for BE patients with mild reflux symptoms and a history of documented
COVID-19.
Terms: <2019 novel coronavirus><2019-nCoV><3-D><3-Dimensional><3D><ACE Inhibitors><Address><Adenocarcinoma Cell><Adenocarcinoma of the Esophagus><Affect><Age><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Angiotensin-Forming Enzyme><Angiotensinogenase><Angiotensins><Barrett Esophagus><Barrett Syndrome><Barrett Ulcer><Benign and Malignant Esophageal Neoplasms><Binding><Body Tissues><CD143 Antigens><COVID-19><COVID19><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Carboxycathepsin><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cleaved cell><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Cohort Studies><Columnar Epithelial-Lined Lower Esophagus><Columnar-Lined Esophagus><Concurrent Studies><Data><Development><Dipeptidyl Peptidase A><Drugs><Epitheliasin Gene><Esophageal Adenocarcinoma><Esophageal Neoplasia><Esophageal Neoplasms><Esophageal Tissue><Esophageal Tumor><Esophageal mucous membrane><Esophagus><Esophagus Neoplasm><Esophagus Tumor><Famotidine><Future><GI microbiome><Gene Expression><General Population><General Public><Histamine-2 Receptor Antagonist><History><Human><Immune><Immunes><Infection><Inflammation><Intracellular Communication and Signaling><Kininase A><Kininase II><Kininase II Antagonists><Kininase II Inhibitors><Malignant Glandular Cell><Mediating><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Neoplasms><Obesity><Omeprazole><Organoids><Outcome><PRSS10><Parents><Pathogenesis><Pathway interactions><Patients><Pepcid><Pepcid AC><Peptidyl-Dipeptidase A><Pharmaceutic Preparations><Pharmaceutical Preparations><Play><Population><Prilosec><Proteins><Proton Pump Inhibitors><Public Health><Publishing><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Recording of previous events><Reflux><Renin><Retrospective cohort study><Risk><Risk Factors><Risk Marker><Role><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Series><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Severe acute respiratory syndrome coronavirus 2><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Symptoms><System><TMPRSS2><TMPRSS2 gene><Tissues><United States><Viral><Virus><Wuhan coronavirus><adiposity><ages><base><biological signal transduction><cleaved><corona virus disease 2019><coronavirus disease 2019><corpulence><corpulency><corpulentia><cytokine><death risk><developmental><digestive tract microbiome><drug/agent><enteric microbiome><esophageal intestinal metaplasia><esophageal mucosa><experiment><experimental research><experimental study><gastrointestinal microbiome><gut microbiome><gut-associated microbiome><high risk><immune microenvironment><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><innovate><innovation><innovative><intestinal biome><intestinal microbiome><male><mortality><mortality risk><neoplasia><neoplastic><neoplastic growth><new marker><notch><notch protein><notch receptors><novel><novel biomarker><novel marker><obese><obese people><obese person><obese population><pandemic><pandemic disease><pathway><patient screening><protein expression><receptor><scRNA-seq><screening><sex><single cell RNA-seq><single cell RNAseq><single-cell RNA sequencing><social role><three dimensional><transcriptome sequencing><tumor immune microenvironment><tumor-immune system interactions>