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

Abstract

BACKGROUNDThe 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.METHODSIndividuals 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.RESULTSTwenty-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.CONCLUSIONTo 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 REGISTRATIONNCT02581137FUNDINGNIH 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 Ew Cohen, H-H Sherry Chow, Scott M Lippman, Eva Szabo
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 17 (09 08 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 34255745 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoglycemic Agents
• RNA, Neoplasm
• Metformin
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Administration, Oral
• Biopsy
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoglycemic Agents (administration & dosage)
• Leukoplakia, Oral (pathology, prevention & control)
• Male
• Metformin (administration & dosage)
• Middle Aged
• Mouth Mucosa (drug effects, metabolism, pathology)
• Precancerous Conditions
• RNA, Neoplasm (genetics)
• Signal Transduction (drug effects)
• Single-Blind Method
• TOR Serine-Threonine Kinases (biosynthesis, genetics)