Abstract 2305: Differential efficacy of metformin versus everolimus in the setting of obesity in a mouse model of serous ovarian cancer
Authors: Wysham Weiya Z. , Zhang Yan , Dickens Hallum K. , Malloy Kimberly M. , Han Xiaoyun , Guo Hui , Gehrig Paola A. , Zhou Chunxiao , Bae-Jump Victoria L. 
Published: August 2015

Objectives: The anti-diabetic drug, metformin, is an AMPK activator with anti-tumorigenic effects. Indirectly, metformin improves insulin resistance and decreases insulin and glucose levels. Directly, metformin activates AMPK, leading to inhibition of the mTOR pathway. Everolimus is a traditional mTOR inhibitor, and its common toxicities include hyperglycemia and insulin resistance. Thus, we compared the efficacy of metformin versus everolimus in a genetically engineered mouse model of serous ovarian cancer (OC) under obese and non-obese conditions.

Methods: We utilized the K18-gT121+/-; p53fl/fl;Brca1fl/fl (KpB) OC mouse model. KpB mice were subjected to 60% calories derived from fat in a high fat diet (HFD) to mimic diet-induced obesity versus 10% calories from fat in a low fat diet (LFD). Mice were treated with placebo, metformin orally (200 mg/kg/day) or everolimus intraperitoneally (3 mg/kg/day) following tumor onset for 4 weeks (N = 8-10 mice/group). Tumor size and volume were recorded weekly. Immunohistochemical analysis was performed on the ovarian tumors after treatment with placebo, metformin or everolimus to assess for effects on proliferation, apoptosis and downstream targets of the mTOR pathway. Individual slides were digitized using the Aperio ScanScope (Aperio Technologies, Vista, CA), and digital images were analyzed using Aperio ImageScope software.

Results: Metformin inhibited tumor growth in the KpB mice fed a LFD (non-obese) and a HFD (obese), after one month of treatment. In the mice fed a HFD, metformin decreased tumor growth by 60% compared to control animals. Tumor growth was only decreased by 32% in the mice fed a LFD. A comparison of the anti-tumorigenic effects of metformin in mice fed a LFD versus a HFD demonstrated that metformin was more efficacious in those mice on the HFD (p = 0.003). Everolimus inhibited tumor growth by 39% and 38% in mice fed a HFD versus LFD, respectively. As compared to placebo-treated mice, metformin and everolimus decreased Ki-67, a marker of cell proliferation, and increased caspase-3, a marker of apoptosis, in the ovarian tumors from obese and non-obese KpB mice. In addition, metformin increased phosphorylation of AMPK, and both metformin and everolimus decreased phosphorylation of S6, a downstream target of the mTOR pathway.

Conclusions: Metformin, an AMPK activator, was found to be more efficacious in the inhibition of ovarian tumor growth in the obese versus non-obese KpB mice, suggesting that obesity may be a biomarker for response to this agent. In contrast, everolimus, a mTOR inhibitor, was found to be equally efficacious in obese and non-obese mice. Further studies are underway to assess the potential differential effects of an AMPK activator versus a mTOR inhibitor on the interrelationship between the metabolic milieu and ovarian tumor growth.

Citation Format: Weiya Z. Wysham, Yan Zhang, Hallum K. Dickens, Kimberly M. Malloy, Xiaoyun Han, Hui Guo, Paola A. Gehrig, Chunxiao Zhou, Victoria L. Bae-Jump. Differential efficacy of metformin versus everolimus in the setting of obesity in a mouse model of serous ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2305. doi:10.1158/1538-7445.AM2015-2305