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An accessible pharmacodynamic transcriptional biomarker for notch target engagement

K Q Tanis1, A A Podtelezhnikov1, S C Blackman1

  • 1Merck & Co., Kenilworth, New Jersey, USA.

Clinical Pharmacology and Therapeutics
|January 15, 2016
PubMed

Insights

Researchers identified a novel biomarker in hair follicles to monitor Notch pathway activity. This biomarker accurately reflects the effects of gamma-secretase inhibitors (GSIs), aiding safe drug development for Alzheimer's disease and cancer.

Area of Science:

  • Pharmacology
  • Biomarker Discovery
  • Molecular Biology

Background:

  • Gamma-secretase is implicated in Alzheimer's disease (AD) amyloid production and Notch signaling's oncogenic roles.
  • Gamma-secretase inhibitors (GSIs) are investigated for AD and oncology, but toxicities necessitate monitoring.
  • A peripheral biomarker for Notch activity is crucial for determining GSI therapeutic windows and dosing.

Purpose of the Study:

  • To investigate the effects of GSI MK-0752 on human blood and hair follicle transcriptomes.
  • To identify a translatable pharmacodynamic biomarker for GSI target engagement.
  • To compare GSI effects on rhesus blood and hair follicles.

Main Methods:

  • Analysis of blood and hair follicle transcriptomes in healthy volunteers treated with GSI MK-0752.
  • Dose-response assessment of GSI effects on gene transcription.
  • Comparison of GSI activity in human and rhesus models.
  • Validation of the identified biomarker in a clinical cohort.

Main Results:

  • MK-0752 significantly impacted hair follicle transcription in a dose-dependent manner, unlike blood.
  • A GSI biomarker identified in hair follicles showed 100% accuracy in a clinical test cohort.
  • The biomarker was also regulated by a different GSI in rhesus models, demonstrating translatability.

Conclusions:

  • Hair follicle RNA serves as a translatable and accessible source for pharmacodynamic biomarkers.
  • This study identified a reliable biomarker for GSI target engagement, enabling better therapeutic monitoring.
  • The findings support the use of hair follicles for assessing GSI activity and optimizing treatment strategies.

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