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Role of drug-dependent transporter modulation on the chemosensitivity of cholangiocarcinoma.

ABSTRACT: Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with limited therapeutic options. Curative therapy is limited to surgery whereas chemotherapy treatments are the election option for unresectable or metastatic cholangiocarcinoma. Cisplatin plus gemcitabine is the reference chemotherapy regimen, albeit the contribution to the median overall survival barely reaches one year. Drug transporters are undoubtedly a limiting step for drug bioavailability and have been clearly related to chemoresistance. Several members of the SoLute Carrier (SLC) superfamily involved in the uptake of anticancer drugs used to treat cholangiocarcinoma are downregulated in these tumors. This study shows the increase in the expression of specific drug transporters exerted by cisplatin treatment thereby enhancing their transport activity. Combination treatments of cisplatin with selected drugs as gemcitabine and sorafenib take in by these transporters at the desired combination schedule induced synergy. These data support the concept that proper administration pattern could favor treatment outcome.

SUBMITTER: Urtasun N

PROVIDER: S-EPMC5685741 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Role of drug-dependent transporter modulation on the chemosensitivity of cholangiocarcinoma.

Urtasun Nerea N Boces-Pascual Clara C Boix Loreto L Bruix Jordi J Pastor-Anglada Marçal M Pérez-Torras Sandra S

Oncotarget 20171006 52

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with limited therapeutic options. Curative therapy is limited to surgery whereas chemotherapy treatments are the election option for unresectable or metastatic cholangiocarcinoma. Cisplatin plus gemcitabine is the reference chemotherapy regimen, albeit the contribution to the median overall survival barely reaches one year. Drug transporters are undoubtedly a limiting step for drug bioavailability and have been clearly related to ...[more]

PMID: 29163820

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Project description:BackgroundOne of the current directions of precision medicine is the use of computational methods to aid in the diagnosis, prognosis, and treatment of disease based on data driven approaches. For instance, in oncology, there has been a particular focus on development of algorithms and biomarkers that can be used for pre-clinical and clinical applications. In particular large-scale omics-based models to predict drug sensitivity in in vitro cancer cell line panels have been used to explore the utility and aid in the development of these models as clinical tools. Additionally, a number of web-based interfaces have been constructed for researchers to explore the potential of drug perturbed gene expression as biomarkers including the NCI Transcriptional Pharmacodynamic Workbench. In this paper we explore the influence of drug perturbed gene dynamics of the NCI Transcriptional Pharmacodynamics Workbench in computational models to predict in vitro drug sensitivity for 15 drugs on the NCI60 cell line panel.ResultsThis work presents three main findings. First, our models show that gene expression profiles that capture changes in gene expression after 24 h of exposure to a high concentration of drug generates the most accurate predictive models compared to the expression profiles under different dosing conditions. Second, signatures of 100 genes are developed for different gene expression profiles; furthermore, when the gene signatures are applied across gene expression profiles model performance is substantially decreased when gene signatures developed using changes in gene expression are applied to non-drugged gene expression. Lastly, we show that the gene interaction networks developed on these signatures show different network topologies and can be used to inform selection of cancer relevant genes.ConclusionOur models suggest that perturbed gene signatures are predictive of drug response, but cannot be applied to predict drug response using unperturbed gene expression. Furthermore, additional drug perturbed gene expression measurements in in vitro cell lines could generate more predictive models; but, more importantly be used in conjunction with computational methods to discover important drug disease relationships.

Dataset Information

Role of drug-dependent transporter modulation on the chemosensitivity of cholangiocarcinoma.

Publications

Role of drug-dependent transporter modulation on the chemosensitivity of cholangiocarcinoma.

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