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About this Publication
Title
Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions.
Pubmed ID
34255745 (View this publication on the PubMed website)
Digital Object Identifier
Publication
JCI Insight. 2021 Jul 13
Authors
Gutkind JS, Molinolo AA, Wu X, Wang Z, Nachmanson D, Harismendy O, Alexandrov LB, Wuertz BR, Ondrey FG, Laronde D, Rock LD, Rosin M, Coffey C, Butler VD, Bengtson L, Hsu CH, Bauman JE, Hewitt SM, Cohen EE, Chow HS, ...show more Lippman SM, Szabo E
Affiliations
  • Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, California, USA.
  • Department of Otolaryngology, Head and Neck Surgery, University of Minnesota (UMN), Minneapolis, Minnesota, USA.
  • Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.
  • British Columbia Cancer Agency (BCCA), British Columbia Agency Research Center, Vancouver, British Columbia, Canada.
  • University of Arizona Cancer Center, Tucson, Arizona, USA.
  • Division of Cancer Prevention and.
  • Center for Cancer Research, NCI, Bethesda, Maryland, USA.
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 (NCT02581137) in individuals with oral premalignant lesions (OPL) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention.

METHODS: Subjects with OPL, otherwise healthy and without diabetes, underwent pre- and post-treatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1,000 mg; week 3-12, 2,000 mg daily). Pre- and post-treatment biopsies, saliva, and blood were obtained for biomarker analysis, including immunohistochemical (IHC) assessment of mTOR signaling and exome sequencing.

RESULTS: Twenty-three participants were evaluable for response. The clinical response rate (defined as ≥50% reduction in lesion size) was 17%. While lower than the proposed threshold for favorable clinical response, the histologic response rate (improvement in histologic grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared to never smokers, current and former smokers had statistically significantly increased histologic responses (p=0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layer of OPL and the histological (p=0.04) and clinical (p=0.01) responses.

CONCLUSIONS: This is the first phase II trial of metformin in individuals with OPL, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent.

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