An accessible pharmacodynamic transcriptional biomarker for notch target engagement.
Clin Pharmacol Ther
; 99(4): 370-80, 2016 Apr.
Article
em En
| MEDLINE
| ID: mdl-26765077
ABSTRACT
γ-Secretase mediates amyloid production in Alzheimer's disease (AD) and oncogenic activity of Notch. γ-Secretase inhibitors (GSIs) are thus of interest for AD and oncology. A peripheral biomarker of Notch activity would aid determination of the therapeutic window and dosing regimen for GSIs, given toxicities associated with chronic Notch inhibition. This study examined the effects of GSI MK-0752 on blood and hair follicle transcriptomes in healthy volunteers. The effects of a structurally diverse GSI on rhesus blood and hair follicles were also compared. Significant dose-related effects of MK-0752 on transcription were observed in hair follicles, but not blood. The GSI biomarker identified in follicles exhibited 100% accuracy in a clinical test cohort, and was regulated in rhesus by a structurally diverse GSI. This study identified a translatable, accessible pharmacodynamic biomarker of GSI target engagement and provides proof of concept of hair follicle RNA as a translatable biomarker source.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Propionatos
/
Inibidores de Proteases
/
Sulfonas
/
Transcrição Gênica
/
Derivados de Benzeno
/
Monitoramento de Medicamentos
/
Folículo Piloso
/
Receptores Notch
/
Secretases da Proteína Precursora do Amiloide
Tipo de estudo:
Clinical_trials
País/Região como assunto:
America do norte
Idioma:
En
Revista:
Clin Pharmacol Ther
Ano de publicação:
2016
Tipo de documento:
Article