title: An accessible pharmacodynamic transcriptional biomarker for notch target engagement.
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.
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: K Q
authors.initials: KQ
authors.lastname: Tanis
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Podtelezhnikov
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Blackman
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hing
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Railkar
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lunceford
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Klappenbach
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: B
authors.initials: B
authors.lastname: Wei
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: A
authors.initials: A
authors.lastname: Harman
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Camargo
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shah
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Finney
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Hardwick
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: A
authors.initials: A
authors.lastname: Loboda
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: J
authors.initials: J
authors.lastname: Watters
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Bergstrom
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: T
authors.initials: T
authors.lastname: Demuth
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Herman
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Strack
authors.affiliation: Merck & Co., Kenilworth, New Jersey, USA.
authors.forename: R
authors.initials: R
authors.lastname: Iannone
mesh_terms: D000293:Adolescent; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D015142:Baltimore; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D054316:Biomarkers, Pharmacological / Q000097:blood; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods; D018859:Hair Follicle / Q000187:drug effects* / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D023421:Models, Animal; D058990:Molecular Targeted Therapy; D020411:Oligonucleotide Array Sequence Analysis; D011422:Propionates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D055815:Young Adult
chemical_list: C554093:3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; D001555:Benzene Derivatives; D054316:Biomarkers, Pharmacological; D011422:Propionates; D011480:Protease Inhibitors; D012333:RNA, Messenger; D051880:Receptors, Notch; D013450:Sulfones; D053829:Amyloid Precursor Protein Secretases