(054) Computational Drug Repurposing for gallbladder cancer integrated with pharmacovigilance approach

Background: Gallbladder cancer (GBC) is a rare but major health problem with a poor prognosis, accounting for about 165,000 cancer deaths annually and comprising 80–95% of biliary tract cancers. Being highly variable in geography and more common in low-income nations, it is one of the most neglected diseases. Moreover, the high recurrence rates, fewer site-specific drugs, and drug resistance prioritize further research in this field and explore the possibilities of molecular targeted therapies.

Objectives: To identify potential targets and inverse signals associated with GBC and screen existing drugs for repurposing based on the identified targets.

Methods: A systematic search was conducted in Gene Expression Omnibus (GEO), and microarray expression profile datasets related to GBC were downloaded. The GEO2R and Venn diagram tools were utilized to filter for differentially expressed genes (DEGs) with a threshold of log (fold change) >1.5 and p < 0.05. Utilizing the Search Tool for the Retrieval of Interacting Genes (STRING), a protein-protein interaction network was constructed between Literature Derived Genes (LDGs) and DEGs and subsequently analyzed using Cytoscape with the CLUEGO plug-in tools. Potential targets verified with the databases GEPIA2 and c-BioPortal. Using the criteria (reporting odds ratio -1.96 SE < 1 and number of reports >3), inverse disproportionality analysis was performed using Open Vigil 2.1 on the FAERS database to extract inverse signals associated with GBC. Subsequently, molecular docking was conducted in Discovery Studio to investigate the target’s interaction with the identified drugs.

Results: TOP2A showed high interactions and was found to be substantially overexpressed in GBC and was shortlisted as the potential target. A catalog of drugs displaying an inverse signal with GBC has been listed, and clinically possible to exhibit the desired pharmacological effect. Among the 54 shortlisted drugs from inverse disproportionality analysis of post marketing surveillance data, Methotrexate and Levothyroxine were spotlighted as a hit due to their highest docking score of -138.13 Kcal/mol and -92.85 Kcal/mol.

Conclusions: This study provides insight into the molecular underpinnings of GBC and suggests the pertinence of Methotrexate and Levothyroxine as a potential repurposable drug in the treatment for GBC. For the results to be strengthened, more in vitro and in vivo research is needed.