Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer

Cancer Medicine

Kevin M. Schuler⁶  Brooke S. Rambally¹  Megan J. DiFurio³  Brante P. Sampey⁴  Paola A. Gehrig⁵  Liza Makowski² 

[1] Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina;Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina;Pinehurst Pathology Center, Pinehurst, North Carolina;Metabolon, Research Triangle Park, North Carolina;Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, North Carolina;Division of Gynecologic Oncology, Good Samaritan Hospital, Cincinnati, Ohio

关键词: Endometrial cancer;    metabolomics;    metformin;    mTOR pathway;   

DOI  :  10.1002/cam4.353

来源: Wiley

【 摘 要 】

Abstract

We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki-67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate-activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre- and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre- and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki-67 staining in their endometrial tumors post-treatment. Metformin decreased expression of phosphorylated (p)-AMPK (P = 0.00001), p-Akt (P = 0.0002), p-S6 (51.2%, P = 0.0002), p-4E-BP-1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformin's effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre-operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC.

【 授权许可】

CC BY   
© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.