Abstract 29: Design of a phase I chemoprevention study of metformin and Li-Fraumeni syndrome (LFS)

Abstract

Abstract Purpose: This phase I chemoprevention pilot study in LFS patients will: 1) assess tolerability of 2000 mg/day of oral metformin in patients with LFS, 2) assess the effect of metformin on circulating serum insulin biomarkers, and 3) use non-invasive technology to assess the effect of metformin on hepatic and skeletal muscle mitochondria in these patients. Background: LFS is a highly-penetrant, autosomal dominant, cancer predisposition disorder characterized by early onset of a spectrum of cancers. Approximately 70% of “classic” LFS families have germline TP53 mutations. Metformin is FDA approved for the treatment of type II diabetes. Epidemiologic studies in diabetic patients have associated metformin use with reduced cancer incidence and mortality, and preclinical research has shown metformin is selectively toxic to cancer cells with loss of p53 function. In non-diabetic patients metformin is well tolerated, does not cause hypoglycemia, and lowers levels of circulating insulin and IGF-1 (insulin-like growth factor 1). In p53+/- mouse models with decreased p53 activity, calorie restriction has resulted in reduction of plasma IGF-1 levels and delayed tumor development, suggesting that lowering IGF-1 may reduce or delay cancer development in individuals with decreased p53 function. Further, p53 also regulates nuclear transcription of mitochondrial proteins and maintains mitochondrial DNA and biogenesis. A recent clinical study indicates that LFS patients with TP53 germline mutations may have increased oxidative phosphorylation capacity in skeletal muscle. Metformin inhibits oxidative phosphorylation in the mitochondria, reducing energy available for rapidly-proliferating cells with mutant TP53. Thus, patients with germline TP53 mutations may benefit from metformin as a chemopreventive agent. Hypotheses/Methods: 1) Metformin will be safe and tolerable in LFS patients with germline mutations in TP53 in oral doses up to 2000 mg/day; 2) Metformin will modulate circulating IGF-1 (insulin-like growth factor 1), IGFBP3 (insulin-like growth factor binding protein 3) and insulin; 3) Metformin will decrease oxidative phosphorylation in both skeletal muscle and hepatic mitochondria. Serum biomarker levels will be assessed by ELISA assays. Hepatic mitochondrial function will be assessed by C-13 methionine breath test. Skeletal muscle mitochondrial function will be assessed by P-31 magnetic resonance spectroscopy. Non-diabetic adults (age >18) with deleterious germline TP53 mutations are eligible. The metformin starting dose is 500 mg/day, with 500 mg/day dose increments every two weeks to a maximum dose of 2000 mg/day. Total study time is 20 weeks. Patients will be on metformin for a total of 14 weeks, after which metformin will be discontinued for 6 weeks. Serum biomarkers and mitochondrial function will be assessed at baseline and weeks 2, 8, 14, and 20. The targeted accrual goal for patients undergoing full dose escalation is ≥22, which will provide an 80% power to detect a change from baseline in each of the three biomarkers equal to 0.75 standard deviations of the change (0.75 effect size) using a two-tailed 0.0167 level paired t-test. This study has been approved by the Institutional Review Board and is open to accrual. Citation Format: Farzana L. Walcott, Paul M. Hwang, Ping-yuan Wang, Sharon A. Savage, Phuong Mai, Seth M. Steinberg, Michael N. Pollak, Philip A. Dennis, Antonio Tito Fojo. Design of a phase I chemoprevention study of metformin and Li-Fraumeni syndrome (LFS). [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 29. doi:10.1158/1538-7445.CANSUSC14-29