Venkatraman, Simran, Balasubramanian, Brinda, Pongchaikul, Pisut 
ORCID: 0000-0001-8757-3554, Tohtong, Rutaiwan and Chutipongtanate, Somchai
(2022)
Molecularly Guided Drug Repurposing for Cholangiocarcinoma: An Integrative Bioinformatic Approach.
GENES, 13 (2).
271-.
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Abstract
<h4>Background</h4>Cholangiocarcinoma (CCA) has a complex immune microenvironment architecture, thus possessing challenges in its characterization and treatment. This study aimed to repurpose FDA-approved drugs for cholangiocarcinoma by transcriptomic-driven bioinformatic approach.<h4>Methods</h4>Cox-proportional univariate regression was applied to 3017 immune-related genes known a priori to identify a list of mortality-associated genes, so-called immune-oncogenic gene signature, in CCA tumor-derived RNA-seq profiles of two independent cohorts. Unsupervised clustering stratified CCA tumors into two groups according to the immune-oncogenic gene signature expression, which then confirmed its clinical relevance by Kaplan-Meier curve. Molecularly guided drug repurposing was performed by an integrative connectivity map-prioritized drug-gene network analysis.<h4>Results</h4>The immune-oncogenic gene signature consists of 26 mortality-associated immune-related genes. Patients with high-expression signature had a poorer overall survival (log-rank <i>p</i> < 0.001), while gene enrichment analysis revealed cell-cycle checkpoint regulation and inflammatory-immune response signaling pathways affected this high-risk group. The integrative drug-gene network identified eight FDA-approved drugs as promising candidates, including Dasatinib a multi-kinase inhibitor currently investigated for advanced CCA with isocitrate-dehydrogenase mutations.<h4>Conclusion</h4>This study proposes the use of the immune-oncogenic gene signature to identify high-risk CCA patients. Future preclinical and clinical studies are required to elucidate the therapeutic efficacy of the molecularly guided drugs as the adjunct therapy, aiming to improve the survival outcome.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | cholangiocarcinoma, connectivity map, drug-gene network, drug repurposing, immuneoncogenic gene signature, transcriptomics, survival analysis |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 20 Jan 2023 10:53 |
| Last Modified: | 03 Feb 2024 08:44 |
| DOI: | 10.3390/genes13020271 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3167201 |
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