Preclinical biomarkers for a cyclin-dependent kinase inhibitor translate to candidate pharmacodynamic biomarkers in phase I patients.
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.
Berkofsky-Fessler
Windy
W
RNA Therapeutics, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA.
Nguyen
Tri Q
TQ
Delmar
Paul
P
Molnos
Juliette
J
Kanwal
Charu
C
DePinto
Wanda
W
Rosinski
James
J
McLoughlin
Patricia
P
Ritland
Steve
S
DeMario
Mark
M
Tobon
Krishna
K
Reidhaar-Olson
John F
JF
Rueger
Ruediger
R
Hilton
Holly
H
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*
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