Preclinical biomarkers for a cyclin-dependent kinase inhibitor translate to candidate pharmacodynamic biomarkers in phase I patients
Autor: | Krishna E. Tobón, Jim Rosinski, Paul Delmar, John F. Reidhaar-Olson, Mark DeMario, Tri Quang Nguyen, Steve R. Ritland, Ruediger Rueger, Patricia Mcloughlin, Wanda DePinto, Charu Kanwal, Holly Hilton, Windy Berkofsky-Fessler, Juliette Molnos |
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Rok vydání: | 2009 |
Předmět: |
Adult
Male Drug Cancer Research Microarray media_common.quotation_subject Phases of clinical research Pharmacology Polymerase Chain Reaction Cyclin-dependent kinase Neoplasms Biomarkers Tumor medicine Humans Aged Oligonucleotide Array Sequence Analysis media_common Aged 80 and over Dose-Response Relationship Drug biology business.industry Kinase Middle Aged Cyclin-Dependent Kinases Clinical trial Pyrimidines Oncology Mechanism of action Pharmacodynamics biology.protein Female medicine.symptom business |
Zdroj: | Molecular Cancer Therapeutics. 8:2517-2525 |
ISSN: | 1538-8514 1535-7163 |
Popis: | A genomics-based approach to identify pharmacodynamic biomarkers was used for a cyclin-dependent kinase inhibitory drug. R547 is a potent cyclin-dependent kinase inhibitor with a potent antiproliferative effect at pharmacologically relevant doses and is currently in phase I clinical trials. Using preclinical data derived from microarray experiments, we identified pharmacodynamic biomarkers to test in blood samples from patients in clinical trials. These candidate biomarkers were chosen based on several criteria: relevance to the mechanism of action of R547, dose responsiveness in preclinical models, and measurable expression in blood samples. We identified 26 potential biomarkers of R547 action and tested their clinical validity in patient blood samples by quantitative real-time PCR analysis. Based on the results, eight genes (FLJ44342, CD86, EGR1, MKI67, CCNB1, JUN, HEXIM1, and PFAAP5) were selected as dose-responsive pharmacodynamic biomarkers for phase II clinical trials. [Mol Cancer Ther 2009;8(9):2517–25] |
Databáze: | OpenAIRE |
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