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Phase II clinical trial of metformin as a cancer stem cell–targeting agent in ovarian cancer
Jason R. Brown, … , Lan G. Coffman, Ronald J. Buckanovich
Jason R. Brown, … , Lan G. Coffman, Ronald J. Buckanovich
Published May 5, 2020
Citation Information: JCI Insight. 2020;5(11):e133247. https://doi.org/10.1172/jci.insight.133247.
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Clinical Medicine Oncology

Phase II clinical trial of metformin as a cancer stem cell–targeting agent in ovarian cancer

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Abstract

BACKGROUND Epidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number and on carcinoma-associated mesenchymal stem cells (CA-MSCs) and clinical outcomes in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC).METHODS Thirty-eight patients with stage IIC (n = 1)/III (n = 25)/IV (n = 12) EOC were treated with either (a) neoadjuvant metformin, debulking surgery, and adjuvant chemotherapy plus metformin or (b) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy plus metformin. Metformin-treated tumors, compared with historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (a) a 2-fold or greater reduction in aldehyde dehydrogenase–positive (ALDH+) CD133+ CSCs and (b) a relapse-free survival at 18 months of more than 50%.RESULTS Metformin was well tolerated. Median progression-free survival was 18.0 months (95% CI 14.0–21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6–70.5). Median overall survival was 57.9 months (95% CI 28.0–not estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH+CD133+ CSCs and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSCs, which prevented CA-MSC–driven chemoresistance in vitro.CONCLUSION Translational studies confirm an impact of metformin on EOC CSCs and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better-than-expected overall survival, supporting the use of metformin in phase III studies.TRIAL REGISTRATION ClinicalTrials.gov NCT01579812.

Authors

Jason R. Brown, Daniel K. Chan, Jessica J. Shank, Kent A. Griffith, Huihui Fan, Robert Szulawski, Kun Yang, R. Kevin Reynolds, Carolyn Johnston, Karen McLean, Shitanshu Uppal, J. Rebecca Liu, Lourdes Cabrera, Sarah E. Taylor, Brian C. Orr, Francesmary Modugno, Pooja Mehta, Michael Bregenzer, Geeta Mehta, Hui Shen, Lan G. Coffman, Ronald J. Buckanovich

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Figure 4

Tumors treated with metformin have decreased cancer stemness.

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Tumors treated with metformin have decreased cancer stemness.
(A) Summar...
(A) Summary of FACS analysis of ALDH+CD133+ CSCs in metformin-treated (n = 22) and matched control ovarian cancers (n = 22) demonstrating a 2.4-fold decrease in CSCs in metformin-treated tumors. (B) Cell viability of tumor cells from metformin-treated patients (n = 6) or control patients (n = 7) grown in suspension, passaged weekly, and treated with cisplatin (5 replicates each). Tumor cells from metformin-treated patients maintain platinum sensitivity with serial passage, while control tumor cells increase platinum resistance over time. (C) Evaluation of ALDH and CD133 expression in metformin-treated and control tumor cells grown in suspension and after serial passages. Metformin-treated samples start at a lower baseline and increase less over time relative to controls. Lines in boxes represent averages. The whiskers depict the minimum and maximum values, and the length of the box represents the interquartile range. Statistical significance between passages was assessed with 2-sided Student’s t tests and comparisons made between metformin and nonmetformin samples at each passage, using 1-/2-way ANOVA and Tukey’s post hoc analysis to determine specific significant differences (P < 0.05). All data are expressed as mean ± SEM.

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