Target Fishing and Drug Repurposing for Pancreatic Ductal Adenocarcinoma: An Integrated Bioinformatic and Computational Approach

Background: Worldwide, over 200000 people die annually of pancreatic ductal adenocarcinoma (PDA), which remains as a major unsolved health problem. The limited survival benefits of conventional cancer treatments in terms of survival, new medications or combinational therapies to combat PDA is the need of the hour. In this scenario, advanced molecular targeted therapeutics necessitate a thorough insight of the molecular mechanism underlying PDA progression.

Objectives: To identify critical PDA genes, followed by screening of drugs acquired through reverse signaling against the identified targets will be a sensible approach.

Methods: GSE125158 Gene expression profile dataset encompassing microarray data of 13 Normal and 17 PDA was analyzed using GEO2R. Differentially Expressed Genes (DEGs) displaying log (fold change) > 1.5 and p < 0.05 were considered as significant. Subsequently, a protein-protein interaction network was constructed between Literature Derived Genes (LDGs) and DEGs using the Search Tool for the Retrieval of Interacting Genes and visualized through Cytoscape. Targets showed high interaction were shortlisted as Crucial targets. Subsequently inverse signal associated with PDA were extracted from the FAERS database using Open Vigil 2.1-MedDRA24. The filtration was done for significant inverse associations (reporting odds ratio -1.96SE < 1 and number of reports >3), and implausibility or clinical infeasibility was also checked. Later the interaction of retrieved target against the identified drugs were studied by molecular docking.

Results: CTBP1 showed high interactions with LDGs is found to be substantially overexpressed in PDA, were shortlisted as the potential target. A list was made with drugs having inverse signal and clinically possible to exhibit the desired pharmacological effect. Among the 45 shortlisted drug, Celecoxib and Rosuvastatin was spotlighted as a hit due to its highest docking score of -7.6 and -7.5. Moreover, Clopidogrel and Fingolimod were showed a docking score of -6.8.

Conclusions: This study reveals the molecular underpinnings of PDA and suggests the pertinence of Celecoxib and Rosuvastatin as a potential repurposable drug in the treatment for PDA. Further in vitro and in vivo studies are required to strengthen the findings.