Abstract 614: Efficacy of metformin in two mouse models of Li-Fraumeni syndrome

Abstract

Abstract Li-Fraumeni Syndrome (LFS) is a rare autosomal hereditary disorder that is commonly associated with germline mutations in the TP53 gene. People with LFS are at high risk to develop a wide range of malignancies including breast cancer, brain tumors, acute leukemias, soft tissue sarcomas, bone sarcomas, and adrenal cortical carcinomas. Although no therapies are approved to treat or prevent LFS, preclinical studies have shown that the anti-diabetic drug metformin is preferentially cytotoxic to p53 null cells in the absence of glucose. This led us to hypothesize that metformin has therapeutic potential in LFS. To confirm the p53 dependence of metformin in vitro, isogenic human and murine cancer cell lines were treated with metformin in the absence or presence of glucose. Metformin induced greater toxicity in p53-deficient cells in a dose-dependent manner. Metformin was then tested in two mouse models that recapitulate the increased tumorigenesis and cancer-related mortality in LFS (p53 mutant mice (p53R172H/+) and p53 null mice (p53-/-)). When administered at 5 mg/ml in drinking water, metformin reached steady state plasma concentrations similar to those in diabetic humans. Biomarker studies showed that oral administration of metformin activated AMPK and inhibited the mTOR pathway in liver tissues. To determine the effects of metformin on overall survival, two sets of studies were performed. For each model, treatment with metformin was begun either late in life (for p53R172H/+, 12 mo; for p53-/-, 4 mo) or early in life (for p53R172H/+, 4 mo; for p53-/-, 1 mo). Mice were treated until death. Long-term oral administration of metformin did not cause weight loss or other discernible toxicity. In the late treatment study, metformin significantly prolonged median survival (for p53R172H/+ mice, 20.6 mo vs. 15.8 mo; p=0.0004)(for p53-/- mice, 9.1 mo vs. 5.3 mo; p=0.0006). Likewise, early treatment with metformin also prolonged median survival (for p53R172H/+ mice, median survival 20.5 compared to 13 months; p=0.0025). The early study with p53-/- mice is ongoing, but median survival is undefined in metformin group, compared to 3.6 mo in control group, p=0.0387). These studies show that metformin is well tolerated and highly effective when given early or late in the life span of two mouse models of LFS. Given that metformin is an inexpensive oral drug that is FDA approved, a pilot clinical trial in LFS is planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 614. doi:10.1158/1538-7445.AM2011-614