Abstract 2067: Hyperpolarized 13C-pyruvate MRS quantitatively monitor the therapeutic efficacy of adjuvant metformin combined RT in brain metastasis from triple negative breast cancer
Authors: Choi Young-suk , Lee Han-Sol , Lee Jung-Sung , Park Hyun-Jin , Lee Ju-Hyun , Wang Eun-Kyung , Yang Seung-Wook , Joe Eunhae , Lee Soo Hyeon , Kim Dong-Hyun , Song Ho-Taek 
Published: May 2015

Abstract
Introduction
The hyperpolarized 13C-pyruvate is a robust imaging biomarker to evaluate the metabolic status of cancer to monitor the anti-cancer therapeutic effect and to predict the prognosis as earliest as possible by 10,000 fold increase of MRS sensitivity. According to the clinical epidemiological research, metformin reduces cancer incidence or mortality in type II diabetes patients. In this study, we investigated the anti-cancer metabolic effect of metformin as an adjuvant for the radiation therapy to treat brain metastasis from triple negative breast cancer in nude mouse model by measuring the metabolic flux through the hyperpolarized 13C-pyruvate MRS.
Methods
Six weeks old BALB/C nude mice were stereotactically implanted 2×105 MDA-MB-231-luciferase breast cancer cells in the striatum of brain. After 1 week from tumor implantation, animals were randomly divided into 4 groups: vehicle (distilled water), oral metformin alone (MET), radiation treatment (RT), and radiation combined with adjuvant oral metformin treatment (METRT). Mice were treated with 300 mg/kg of oral metformin for 5 days in a week from week 1 until when the animals die. MRI and 13C MRS was performed at week 2 and week 3, before and after treatment. Brain tumors were irradiated at week 2 with 3Gy for 5 consecutive days. MRI and MRS was performed at 9.4T Bruker MRI scanner using 20mm surface dual tuned 1H-13C coil. 75mmole of hyperpolarized [1-13C] pyruvate was injected via tail vein in all mice. Metabolic flux was calculated as lactate/pyruvate ratio. The progression and the response to treatment was also monitored by bioluminescence imaging. Paraffin sections were stained with H&E for histological evaluation.
Results
There was no difference in tumor growth and metabolic flux rate between vehicle and MET alone groups. Vehicle group showed 260% increase in tumor mass, whereas RT group showed only 39% increase in tumor volume. 13C MRS showed 60% decrease in lactate/pyruvate flux ratio in RT group, whereas vehicle group showed 60% increase in metabolic flux ratio. Interestingly, the tumor volume was significantly regressed and 13C-lactate flux was significantly decreased in METRT group after treatment. Bioluminescence imaging showed time-dependent increasing flux in vehicle group, but RT and METRT groups showed decreased photon flux activity. In comparison of METRT with RT alone group, bioluminescence activity was significantly decreased in METRT group. H&E staining of histological sections showed significant tumor necrosis and decreased cellularity in METRT group.
Conclusion
Hyperpolarized 13C-pyruvate MRS informs the adjuvant therapeutic effect of metformin and RT in brain metastasis from triple negative breast cancer.
Citation Format: Young-suk Choi, Han-Sol Lee, Jung-Sung Lee, Hyun-Jin Park, Ju-Hyun Lee, Eun-Kyung Wang, Seung-Wook Yang, Eunhae Joe, Soo Hyeon Lee, Dong-Hyun Kim, Ho-Taek Song. Hyperpolarized 13C-pyruvate MRS quantitatively monitor the therapeutic efficacy of adjuvant metformin combined RT in brain metastasis from triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2067. doi:10.1158/1538-7445.AM2014-2067