Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions
J. Silvio Gutkind, … , Scott M. Lippman, Eva Szabo
J. Silvio Gutkind, … , Scott M. Lippman, Eva Szabo
Published July 13, 2021
Citation Information: JCI Insight. 2021;6(17):e147096. https://doi.org/10.1172/jci.insight.147096.
View: Text | PDF
Clinical Medicine Clinical trials

Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions

  • Text
  • PDF
Abstract

BACKGROUND The aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention.METHODS Individuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3–12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing.RESULTS Twenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses (P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological (P = 0.04) and clinical (P = 0.01) responses.CONCLUSION To our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent.TRIAL REGISTRATION NCT02581137FUNDING NIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870

Authors

J. Silvio Gutkind, Alfredo A. Molinolo, Xingyu Wu, Zhiyong Wang, Daniela Nachmanson, Olivier Harismendy, Ludmil B. Alexandrov, Beverly R. Wuertz, Frank G. Ondrey, Denise Laronde, Leigha D. Rock, Miriam Rosin, Charles Coffey, Valerie D. Butler, Lisa Bengtson, Chiu-Hsieh Hsu, Julie E. Bauman, Stephen M. Hewitt, Ezra E.W. Cohen, H-H. Sherry Chow, Scott M. Lippman, Eva Szabo

×

Full Text PDF | Download (5.29 MB)


Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts