Abstract
A transcriptional signature of the pan-cyclin-dependent kinase (Cdk) inhibitor PHA-793887 was evaluated as a potential pharmacodynamic and/or response biomarker in tumor and skin biopsies from patients treated in a phase I clinical study. We first analyzed the expression of a number of known E2F-dependent genes that were predicted to be modulated after Cdk2 and Cdk4 inhibition in xenograft tumor and skin samples of mice treated with the compound. This panel of 58 selected genes was then analyzed in biopsies from seven patients treated with PHA-793887 in a phase I dose escalation clinical trial in solid tumors. Quantitative real-time PCR or microarray analyses were done in paired skin and tumor biopsies obtained at baseline and at cycle 1. Analysis by quantitative real-time PCR of the signature in skin biopsies of patients treated at three different doses showed significant transcriptional downregulation with a dose-response correlation. These data show that PHA-793887 modulates genes involved in cell cycle regulation and proliferation in a clinical setting. The observed changes are consistent with its mechanism of action and correlate with target modulation in skin and with clinical benefit in tumors.
Highlights
Gene expression analysis of tumor biopsies has been successfully applied to provide improved classification of tumor types and subpopulations and to the identification of prognostic and predictive biomarkers that will significantly contribute to patient stratification and possibly lead to identification of new pharmacologic targets [1, 2]
To identify genes modulated by Cdk2 and Cdk4 inhibition, we exploited the available literature to select a panel enriched with known E2Fdependent genes involved in cell cycle regulation and transcriptional control, DNA replication and repair, chromosome organization, mitosis, and apoptosis (Table 1; refs. 11–16)
We analyzed by quantitative real-time PCR (qRT-PCR) the expression of these genes in the A2780 tumor cell line treated with 1 μmol/L PHA-793887 in vitro, a concentration that was confirmed by Western blot analysis to partially inhibit phosphorylation of the Cdk2 substrates Rb and NPM (Supplementary Fig. S1)
Summary
Gene expression analysis of tumor biopsies has been successfully applied to provide improved classification of tumor types and subpopulations and to the identification of prognostic and predictive biomarkers that will significantly contribute to patient stratification and possibly lead to identification of new pharmacologic targets [1, 2]. An early development biomarker analysis that attempts to replicate preclinical pharmacokinetic/pharmacodynamic models requires pretreatment and posttreatment samples, limiting the analysis to patients for which tumor biopsies can be obtained. For. Authors' Affiliations: 1Business Unit Oncology, Nerviano Medical Sciences S.r.l., Nerviano (MI), Italy; 2Bioinformatics and Genomics Unit, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Orbassano (TO), Italy; 3Genextra Group, Milano, Italy; 4Drug Metabolism, Pharmacokinetics and Attrition-Reducing Technologies, Accelera, Nerviano, Italy; and 5Institut Gustave Roussy, Villejuif Cedex, France.
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