Novel approach for management of endometrial cancer : drug repositioning of metformin

[SUMMARY] Metformin, a mainstay drug used clinically for over 60 years, improves insulin sensitivity and is widely prescribed for type 2 diabetes mellitus. Since population-based studies have suggested that metformin decreases the incidence of cancer and cancer-related mortality in patients with diabetes, metformin has attracted attention in cancer research as well. Endometrial cancer（EC） is the most common gynecological cancer and exhibits the strongest association with obesity and insulin resistance, and as such, is hypothesized as a suitable target cancer for metformin evaluation. In the in vitro experiment, metformin suppressed EC cell proliferation via AMPK-dependent and independent pathways, as in other cancer cell lines. Metformin also showed an additive effect on cell proliferation when administered in combination with anticancer drugs. Since the dose that was necessary to suppress cell proliferation in vitro was notably higher than the serum concentration in metformin-administered patients, we next examined whether a clinical dose of metformin was effective in patients. Preoperative metformin treatment decreased serum-stimulated DNA synthesis and significantly reduced Ki-67 and topoisomerase IIα levels in endometrial tissues, indicating reduced growth-supporting potential in the serum of patients with EC. Collectively, metformin may act both directly and indirectly, with both pathways contributing to its anti-neoplastic activity. In a clinical setting, we conducted a phase II study of medroxyprogesterone（MPA）in combination with metformin as a fertility-sparing treatment for patients with atypical endometrial hyperplasia or EC. Combining metformin with MPA reduced relapse after remission and improved patient metabolic status. Following the trial, we have initiated a prospective randomized, open, blinded-endpoint, dose-response trial（phaseIIb）of MPA plus metformin（jRCT 2031190065）to verify an appropriate metformin dose in a fertility-sparing treatment, which is ongoing.

https://opac.ll.chiba-u.jp/da/curator/108009/

https://opac.ll.chiba-u.jp/da/curator/108009/S03035476-96E-2-P33.pdf

The Chiba Medical Society

千葉医学会

学術雑誌論文

AN00142148

Chiba medical journal

96E

2

33

40

2020-04-10

10.20776/S03035476-96E-2-P33

publisher

Chiba Medical Journal (ONLINE ISSN 2433-4235)