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An accessible pharmacodynamic transcriptional biomarker for notch target engagement
Author(s) -
Tanis KQ,
Podtelezhnikov AA,
Blackman SC,
Hing J,
Railkar RA,
Lunceford J,
Klappenbach JA,
Wei B,
Harman A,
Camargo LM,
Shah S,
Finney EM,
Hardwick JS,
Loboda A,
Watters J,
Bergstrom DA,
Demuth T,
Herman GA,
Strack PR,
Ian R
Publication year - 2016
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.335
Subject(s) - biomarker , pharmacodynamics , notch signaling pathway , hair follicle , transcriptome , biology , medicine , cancer research , oncology , pharmacology , pharmacokinetics , gene , receptor , gene expression , genetics
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.