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Molecularly Guided Drug Repurposing for Cholangiocarcinoma: An Integrative Bioinformatic Approach
Simran Venkatraman1, Brinda Balasubramanian1, Pisut Pongchaikul2,3
1Graduate Program in Molecular Medicine, Faculty of Science Joint Program Faculty of Medicine Ramathibodi Hospital, Faculty of Medicine Siriraj Hospital, Faculty of Dentistry, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
Background:
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.
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.
Insights
This study identified a 26-gene immune signature predicting poor survival in cholangiocarcinoma (CCA) patients. Repurposing FDA-approved drugs, including Dasatinib, shows promise for treating this complex cancer.
Area of Science:
- Oncology
- Bioinformatics
- Immunology
Background:
- Cholangiocarcinoma (CCA) presents a complex tumor immune microenvironment, complicating diagnosis and treatment.
- Transcriptomic data and bioinformatics approaches are crucial for understanding CCA's immune landscape.
- Repurposing existing FDA-approved drugs offers a potential strategy to overcome treatment challenges in CCA.
Purpose of the Study:
- To identify a novel immune-related gene signature associated with mortality in cholangiocarcinoma.
- To stratify cholangiocarcinoma patients into distinct risk groups based on immune gene expression.
- To discover FDA-approved drugs that can be repurposed for cholangiocarcinoma treatment using a transcriptomic-driven approach.
Main Methods:
- Cox-proportional univariate regression analysis of 3017 immune-related genes in two independent CCA cohorts.
- Unsupervised clustering to stratify tumors based on the identified immune-oncogenic gene signature.
- Integrative connectivity map and drug-gene network analysis for molecularly guided drug repurposing.
Main Results:
- A 26-gene immune-oncogenic gene signature was identified, significantly correlating with overall survival in CCA patients (log-rank p < 0.001).
- High expression of the signature was associated with poorer survival and linked to cell-cycle checkpoint regulation and inflammatory-immune response pathways.
- Eight FDA-approved drugs, including Dasatinib, were identified as promising candidates for repurposing in advanced CCA.
Conclusions:
- The developed immune-oncogenic gene signature can identify high-risk cholangiocarcinoma patients.
- Further preclinical and clinical investigations are necessary to validate the efficacy of the identified repurposed drugs as adjunct therapies.
- This study provides a foundation for improving survival outcomes in cholangiocarcinoma through targeted, molecularly guided drug repurposing.
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