1. An accessible pharmacodynamic transcriptional biomarker for notch target engagement.
- Author
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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, and Iannone R
- Subjects
- Adolescent, Adult, Amyloid Precursor Protein Secretases metabolism, Animals, Baltimore, Benzene Derivatives administration & dosage, Benzene Derivatives blood, Benzene Derivatives pharmacokinetics, Biomarkers, Pharmacological blood, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Gene Expression Profiling methods, Hair Follicle metabolism, Healthy Volunteers, Humans, Macaca mulatta, Male, Models, Animal, Molecular Targeted Therapy, Oligonucleotide Array Sequence Analysis, Propionates administration & dosage, Propionates blood, Propionates pharmacokinetics, Protease Inhibitors administration & dosage, Protease Inhibitors blood, Protease Inhibitors pharmacokinetics, RNA, Messenger biosynthesis, RNA, Messenger blood, Receptors, Notch metabolism, Sulfones administration & dosage, Sulfones blood, Sulfones pharmacokinetics, Young Adult, Amyloid Precursor Protein Secretases antagonists & inhibitors, Benzene Derivatives pharmacology, Drug Monitoring methods, Hair Follicle drug effects, Propionates pharmacology, Protease Inhibitors pharmacology, Receptors, Notch antagonists & inhibitors, Sulfones pharmacology, Transcription, Genetic drug effects
- 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., (© 2016 American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2016
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