Keywords

Barrett's Esophagus, Activin A, Esophageal Adenocarcinoma

Abstract

In 2020, approximately 1.03 billion cases of Gastro-esophageal Reflux Disease (GERD) were reported worldwide, representing a significant global health burden. Chronic GERD is a potent initiator of Barrett’s Esophagus (BE), a precancerous condition in which the squamous epithelium is converted into columnar-like epithelium in the distal esophagus in response to reflux injury. Barrett’s Esophagus is the only known precursor to Esophageal Adenocarcinoma (EAC), a disease with a five-year survival rate of 21%. First line treatments focus on acid suppression and endoscopic mucosal resection but did not result in a decrease of EAC incidence highlighting the importance of new therapeutics. Previous studies in our laboratory have shown an increase in endogenous secretion of Activin A (ActA), a cytokine that promotes inflammation and wound healing in the distal esophagus, in experimental GERD. Furthermore, upregulation of the ActA gene, Inhibin A (INHBA), is reported throughout the progression of BE and EAC afflicted tissues, leading us to hypothesize inhibition of ActA in the progression from BE to EAC could be promising novel therapeutic strategy. We established pre-clinical three-dimensional spheroid cultures of human esophageal cell lines representing the progression from normal to late-stage BE to assess the functional consequences of ActA inhibition utilizing Garetosmab (REGN2477), an ActA neutralizing antibody. Additionally, we utilized a transgenic mouse model of BE challenged with a high fat diet and simulated GERD to assess the functional consequences of a bivalent ActA and myostatin neutralizing antibody, V08-035 (Vaxxinity Inc.). We observed a reduction in BE cell growth mediated in part by cellular senescence and apoptosis which resulted in decrease spheroid size and diameter. Further, we observed alterations in BE mouse weight and murine serum secretome mirroring in vitro findings using human cell lines. Our data suggests targeting ActA signaling with neutralizing therapeutics could prevent the progression of BE.

Completion Date

2025

Semester

Summer

Committee Chair

Claudia Andl

Degree

Master of Science (M.S.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Identifier

DP0029541

Language

English

Document Type

Thesis

Campus Location

Orlando (Main) Campus

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