(A-226) Target Fishing and Drug Repurposing for Esophageal Adenocarcinoma: An Integrated Bioinformatic and Pharmacovigilance Approach

Background: Esophageal adenocarcinoma (EAC) is a malignant epithelial tumor of the esophagus with glandular differentiation. Globally, esophageal cancer accounts for about 511,054 new cases and approximately 445,391 deaths, with a rapid rise in EAC in many developed countries, including Europe, North America, and Australia.

Objectives: Identify potential targets for EAC and repurpose drugs sourced from real-world data by screening them against these identified targets.

Methods: A systematic search was performed in the Gene Expression Omnibus (GEO), identifying datasets relevant to EAC. The GEO2R and Venn diagram tools were utilized to filter for differentially expressed genes. Using the Search Tool for the Retrieval of Interacting Genes (STRING), a protein-protein interaction network was constructed and subsequently analyzed using Cytoscape. Potential targets verified with the databases GEPIA2 and cBioportal. Inverse disproportionality analysis was performed using OpenVigil to extract inverse signals associated with EAC. Subsequently, the interaction between repurposable drugs and EAC targets was virtually demonstrated via molecular docking and molecular dynamic simulation conducted in Biovia Discovery Studio 2024, to investigate the target’s interaction with the identified drugs.

Results: Epidermal Growth Factor Receptor (EGFR), significantly overexpressed in EAC, was pinpointed as a potential target. According to the GEPIA2 database, overexpression of EGFR is associated with reduced survival of EAC patients, and by analysing in cBioportal over 17% of gene alteration in EGFR is amplification. Overall, 15 drugs with Drug Event >3 and Lower Bound ROR < 1 were shortlisted as prospective repurposable drugs as per the Real-World Data obtained from FAERs. Further, in-silico studies identified Levothyroxine with a docking score of 63.73 kCal/mol with a lower root-mean-square deviation, root-mean-square fluctuation, and radius of gyration value as a potential repurposable drug.

Conclusions: This study provides insight into the molecular underpinning of EAC and suggests the pertinence of levothyroxine as a potential repurposable drug in treating it. Further in vitro and in vivo research is needed to strengthen these findings.