TY - JOUR
T1 - Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions
AU - Gutkind, J. Silvio
AU - Molinolo, Alfredo A.
AU - Wu, Xingyu
AU - Wang, Zhiyong
AU - Nachmanson, Daniela
AU - Harismendy, Olivier
AU - Alexandrov, Ludmil B.
AU - Wuertz, Beverly R.
AU - Ondrey, Frank G.
AU - Laronde, Denise
AU - Rock, Leigha D.
AU - Rosin, Miriam
AU - Coffey, Charles
AU - Butler, Valerie D.
AU - Bengtson, Lisa
AU - Hsu, Chiu Hsieh
AU - Bauman, Julie E.
AU - Hewitt, Stephen M.
AU - Cohen, Ezra E.W.
AU - Chow, H. H.Sherry
AU - Lippman, Scott M.
AU - Szabo, Eva
N1 - Publisher Copyright:
© 2021, Gutkind et al.
PY - 2021/9/8
Y1 - 2021/9/8
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.147096
DO - 10.1172/jci.insight.147096
M3 - Article
C2 - 34255745
AN - SCOPUS:85114607071
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 17
M1 - e147096
ER -