Preclinical biomarkers for a cyclin-dependent kinase inhibitor translate to candidate pharmacodynamic biomarkers in phase I patients

被引：19

作者：

Berkofsky-Fessler, Windy

Nguyen, Tri Q. ^{[4
]}

Delmar, Paul ^{[4
]}

Molnos, Juliette ^{[4
]}

Kanwal, Charu

DePinto, Wanda ^{[2
]}

Rosinski, James ^{[3
]}

McLoughlin, Patricia ^{[4
]}

Ritland, Steve ^{[2
]}

DeMario, Mark ^{[2
]}

Tobon, Krishna ^{[6
]}

Reidhaar-Olson, John F.

Rueger, Ruediger ^{[5
]}

Hilton, Holly ^{[1
]}

机构：

[1] Hoffmann La Roche Inc, RNA Therapeut, Nutley, NJ 07110 USA

[2] Pharma Dev, Nutley, NJ USA

[3] In Silico Sci, Nutley, NJ USA

[4] F Hoffmann La Roche Ltd, Mol Med Labs, Basel, Switzerland

[5] Roche Diagnost GmbH, Pharma Dev, Penzberg, Germany

[6] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ 07103 USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2009年 / 8卷 / 09期

关键词：

CELL PROLIFERATION; ANTITUMOR-ACTIVITY; GENE-EXPRESSION; TARGET GENES; P-TEFB; CANCER; GROWTH; EGR-1; IDENTIFICATION; ELONGATION;

D O I：

10.1158/1535-7163.MCT-09-0083

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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]

引用

页码：2517 / 2525

页数：9

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