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The NCI Transcriptional Pharmacodynamics Workbench: A Tool to Examine Dynamic Expression Profiling of Therapeutic
Anne Monks1, Yingdong Zhao2, Curtis Hose1
1Molecular Pharmacology Group, Frederick National Laboratory for Cancer Research sponsored by the NCI, Frederick, Maryland.
Abstract:
: The intracellular effects and overall efficacies of anticancer therapies can vary significantly by tumor type. To identify patterns of drug-induced gene modulation that occur in different cancer cell types, we measured gene-expression changes across the NCI-60 cell line panel after exposure to 15 anticancer agents. The results were integrated into a combined database and set of interactive analysis tools, designated the NCI Transcriptional Pharmacodynamics Workbench (NCI TPW), that allows exploration of gene-expression modulation by molecular pathway, drug target, and association with drug sensitivity. We identified common transcriptional responses across agents and cell types and uncovered gene-expression changes associated with drug sensitivity. We also demonstrated the value of this tool for investigating clinically relevant molecular hypotheses and identifying candidate biomarkers of drug activity. The NCI TPW, publicly available at https://tpwb.nci.nih.gov, provides a comprehensive resource to facilitate understanding of tumor cell characteristics that define sensitivity to commonly used anticancer drugs. SIGNIFICANCE: The NCI Transcriptional Pharmacodynamics Workbench represents the most extensive compilation to date of directly measured longitudinal transcriptional responses to anticancer agents across a thoroughly characterized ensemble of cancer cell lines.
Insights
This study details the NCI Transcriptional Pharmacodynamics Workbench (NCI TPW), a tool analyzing gene expression changes from anticancer drugs across diverse cancer cell lines to understand drug sensitivity and identify biomarkers.
Area of Science:
- Pharmacogenomics
- Cancer Biology
- Bioinformatics
Background:
- Anticancer therapy efficacy varies by tumor type.
- Understanding drug-induced gene modulation is crucial for personalized medicine.
Purpose of the Study:
- To identify patterns of drug-induced gene modulation across different cancer cell types.
- To develop a resource for exploring drug sensitivity and gene expression associations.
Main Methods:
- Gene-expression profiling of the NCI-60 cell line panel after exposure to 15 anticancer agents.
- Integration of data into the NCI Transcriptional Pharmacodynamics Workbench (NCI TPW).
- Analysis of gene modulation by pathway, drug target, and drug sensitivity.
Main Results:
- Identified common transcriptional responses to anticancer agents across cell types.
- Uncovered gene-expression changes correlated with drug sensitivity.
- Demonstrated the utility of NCI TPW for hypothesis testing and biomarker discovery.
Conclusions:
- The NCI TPW is a comprehensive resource for understanding tumor cell characteristics influencing sensitivity to anticancer drugs.
- This workbench facilitates research into drug mechanisms and personalized cancer treatment strategies.
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