Abstract 4088: Targeting glutamine metabolism in breast cancer

Abstract Background: Unlike normal cells, most cancer cells primarily metabolize glucose by glycolysis rather than oxidative phosphorylation (Warburg effect). The cancer cells are reprogrammed to acquire these fundamental metabolic alterations during malignant transformation via different mechanisms. These mechanisms include mitochondrial defects and malfunction, adaptation to a hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Cancer cells also rely on glutamine for anabolism and ATP synthesis. Recent studies have shown that inhibiting glycolytic pathways leads to a significant inhibition of growth of tumor xenografts. Our group has previously shown the MYC oncogene activates glutamine metabolism which serves as a major energy source in transformed cells. Objective: Examine the antitumor effect of a glutamine metabolic inhibitor, aminooxyacetate (AOA; aminotransferases/malate-aspartate shuttle inhibitor), alone and in combination with chemotherapy (doxorubicin and carboplatin) in a breast cancer xenograft model. Methods: Immunodeficient mice bearing MDA-MB-231 breast cancer cells were treated with AOA alone, doxorubicin or carboplatin alone, or AOA in combination with the chemotherapeutic agent for four weeks. The tumors were evaluated for histopathological and molecular alterations. Statistical analysis: Tumor growth was analyzed using a mixed-effects model for repeated measures data to account for dependence among observations within the same animal. Results: We observed a significant inhibition of tumor volume in mice treated with AOA in combination with doxorubicin or carboplatin compared to groups receiving single drugs (p<0.01). Western blot analysis of tumors treated with drug combinations showed decreased cyclin D1 level and increased p21 levels. Changes in key components of the glycolytic pathway are being examined. Conclusion: Our results suggest that targeting the metabolic pathway results in significant tumor inhibition in preclinical models of breast cancer and potentially could serve as attractive therapeutic targets for breast cancer. 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 4088. doi:10.1158/1538-7445.AM2011-4088