title: Preclinical biomarkers for a cyclin-dependent kinase inhibitor translate to candidate pharmacodynamic biomarkers in phase I patients.
abstract: 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.
authors.affiliation: RNA Therapeutics, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA.
authors.forename: Windy
authors.initials: W
authors.lastname: Berkofsky-Fessler
authors.forename: Tri Q
authors.initials: TQ
authors.lastname: Nguyen
authors.forename: Paul
authors.initials: P
authors.lastname: Delmar
authors.forename: Juliette
authors.initials: J
authors.lastname: Molnos
authors.forename: Charu
authors.initials: C
authors.lastname: Kanwal
authors.forename: Wanda
authors.initials: W
authors.lastname: DePinto
authors.forename: James
authors.initials: J
authors.lastname: Rosinski
authors.forename: Patricia
authors.initials: P
authors.lastname: McLoughlin
authors.forename: Steve
authors.initials: S
authors.lastname: Ritland
authors.forename: Mark
authors.initials: M
authors.lastname: DeMario
authors.forename: Krishna
authors.initials: K
authors.lastname: Tobon
authors.forename: John F
authors.initials: JF
authors.lastname: Reidhaar-Olson
authors.forename: Ruediger
authors.initials: R
authors.lastname: Rueger
authors.forename: Holly
authors.initials: H
authors.lastname: Hilton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C515235:(4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl)(2,3-difluoro-6-methoxyphenyl)methanone; D014408:Biomarkers, Tumor; D011743:Pyrimidines; D018844:Cyclin-Dependent Kinases