Drug repositioning for esophageal squamous cell carcinoma

Abstract

Esophageal cancer (EC) remains a significant challenge globally, having the 8th highest incidence and 6th highest mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common form of EC in Asia. Crucially, more than 90% of EC cases in China are ESCC. The high mortality rate of EC is likely due to the limited number of effective therapeutic options. To increase patient survival, novel therapeutic strategies for EC patients must be devised. Unfortunately, the development of novel drugs also presents its own significant challenges as most novel drugs do not make it to market due to lack of efficacy or safety concerns. A more time and cost-effective strategy is to identify existing drugs, that have already been approved for treatment of other diseases, which can be repurposed to treat EC patients, with drug repositioning. This can be achieved by comparing the gene expression profiles of disease-states with the effect on gene-expression by a given drug. In our analysis, we used previously published microarray data and identified 167 differentially expressed genes (DEGs). Using weighted key driver analysis, 39 key driver genes were then identified. These driver genes were then used in Overlap Analysis and Network Analysis in Pharmomics. By extracting drugs common to both analyses, 24 drugs are predicted to demonstrate therapeutic effect in EC patients. Several of which have already been shown to demonstrate a therapeutic effect in EC, most notably Doxorubicin, which is commonly used to treat EC patients, and Ixazomib, which was recently shown to induce apoptosis and supress growth of EC cell lines. Additionally, our analysis predicts multiple psychiatric drugs, including Venlafaxine, as repositioned drugs. This is in line with recent research which suggests that psychiatric drugs should be investigated for use in gastrointestinal cancers such as EC. Our study shows that a drug repositioning approach is a feasible strategy for identifying novel ESCC therapies and can also improve the understanding of the mechanisms underlying the drug targets.

Current Status and Future Prospects for Esophageal Cancer

“…Finally, drug repositioning has been recently suggested as a feasible and cost-effective strategy to identify novel treatments for EC [295]. This approach is based on identifying existing drugs that have already been approved for treating other conditions, which can be repurposed to treat patients with EC [295]. In this approach, the gene expression profiles of disease states are compared with the effect on gene expression by a given drug [295].…”

“…This approach is based on identifying existing drugs that have already been approved for treating other conditions, which can be repurposed to treat patients with EC [295]. In this approach, the gene expression profiles of disease states are compared with the effect on gene expression by a given drug [295].…”

Venlafaxine, an anti-depressant drug, induces apoptosis in MV3 human melanoma cells through JNK1/2-Nur77 signaling pathway

“…One way to expedite drug development is to discover new uses for approved or investigational drugs. Recently, a study conducted by Bennett et al revealed that predicted venlafaxine as an anti-cancer compound ( Bennett et al, 2022 ). Venlafaxine is a serotonin and norepinephrine reuptake inhibitor ( Figure 1A ) and has been used in therapy as an anti-depressant drug since 1993 ( Roseboom and Kalin, 2000 ).…”

PLCD3 promotes malignant cell behaviors in esophageal squamous cell carcinoma via the PI3K/AKT/P21 signaling

“…There are two major subtypes of esophageal cancer, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). More than 90% of all esophageal cancers in China are ESCC [ 1 ]. Because of the lack of clear symptoms and sensitive screening methods at an early stage, most ESCC patients are at an advanced stage of diagnosis.…”