Molecularly Guided Drug Repurposing for Cholangiocarcinoma: An Integrative Bioinformatic Approach
Background: Cholangiocarcinoma (CCA) has a complex immune microenvironment archi-tecture, thus possessing challenges in its characterization and treatment. This study aimed to repur-pose FDA-approved drugs for cholangiocarcinoma by transcriptomic-driven bioinformatic approach. Methods: Cox-proportio...
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| Format: | Article |
| Published: |
2023
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| Online Access: | https://repository.li.mahidol.ac.th/handle/123456789/83839 |
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| Institution: | Mahidol University |
| Summary: | Background: Cholangiocarcinoma (CCA) has a complex immune microenvironment archi-tecture, thus possessing challenges in its characterization and treatment. This study aimed to repur-pose FDA-approved drugs for cholangiocarcinoma by transcriptomic-driven bioinformatic approach. Methods: 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. Results: 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 p < 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. Conclusion: 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. |
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