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

• Published in: Cancer medicine (Malden, MA) Vol. 4; no. 2; pp. 161 - 173
• Main Authors: Schuler, Kevin M., Rambally, Brooke S., DiFurio, Megan J., Sampey, Brante P., Gehrig, Paola A., Makowski, Liza, Bae‐Jump, Victoria L.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2015; BlackWell Publishing Ltd
• Subjects: Adenosine kinase; Adult; Aged; AKT protein; AMP; Antidiabetics; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Biomarkers, Tumor - blood; Cancer Research; Cell Proliferation - drug effects; Clinical trials; Endometrial cancer; Endometrial Neoplasms - complications; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - pathology; Endometrium; Estrogen receptors; Female; Glycogen; Health risk assessment; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Immunohistochemistry; Insulin resistance; Kinases; Lipid metabolism; Lipolysis; Menopause; Metabolomics; Metformin; Metformin - administration & dosage; Metformin - pharmacology; Middle Aged; mTOR pathway; Obesity; Obesity - blood; Obesity - complications; Obesity - drug therapy; Original Research; Oxidation; Patients; Preoperative Care; Progesterone; Protein kinase; Rapamycin; Signal Transduction - drug effects; TOR protein; Tumors; Young Adult; United States > US; mTOR pathway; metformin; Endometrial cancer; metabolomics
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.353

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. Metformin significantly reduced proliferation, as assessed by Ki‐67 staining, in a preoperative window study in obese endometrial cancer patients, with parallel effects on inhibition of the mTOR pathway. Differences were found in the metabolic effects of metformin in the serum and endometrial tumors of responders versus nonresponders to treatment, including increased lipolysis, fatty acid oxidation, and glycogen metabolism in responders. This study provides support for therapeutic clinical trials of metformin in this obesity‐driven disease.