title: Transcriptional analysis of an E2F gene signature as a biomarker of activity of the cyclin-dependent kinase inhibitor PHA-793887 in tumor and skin biopsies from a phase I clinical study.
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.
authors.affiliation: Business Unit Oncology, Nerviano Medical Sciences srl, Nerviano (MI), Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Locatelli
authors.forename: Roberta
authors.initials: R
authors.lastname: Bosotti
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
authors.forename: Maria G
authors.initials: MG
authors.lastname: Brasca
authors.forename: Raffaele
authors.initials: R
authors.lastname: Calogero
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Matteo
authors.initials: M
authors.lastname: Bertolotti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scacheri
authors.forename: Angela
authors.initials: A
authors.lastname: Scaburri
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Thierry
authors.initials: T
authors.lastname: De Baere
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001706:Biopsy; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D050684:E2F Transcription Factors / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015533:Transcriptional Activation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D050684:E2F Transcription Factors; C549971:N-(6,6-dimethyl-5-((1-methylpiperidin-4-yl)carbonyl)-1,4,5,6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-methylbutanamide; D011720:Pyrazoles; D011758:Pyrroles; D018844:Cyclin-Dependent Kinases