Abstract 5421: Targeting glucose and glutamine for the metabolic management of systemic metastatic cancer

Abstract

Abstract Metastatic cancer is a major cause of morbidity and mortality. Current therapeutic options consist of chemotherapy, radiation, or targeted therapies. However, these therapies are often toxic, effective over a small range of cancer types, or result in drug resistance. Therefore, a more global, less toxic strategy for the management of metastatic cancer is required. Though most cancers display increased glucose metabolism, glutamine is also a major energy substrate for many cancers. We evaluated the anti-metastatic potential of 6-diazo-5-oxo-L-norleucine (DON), a glutamine analog, using the new VM mouse model of systemic metastasis. In addition we evaluated the combined inhibition of glucose and glutamine metabolism by treating mice with both DON, which targets glutamine, and calorie restriction (CR), which reduces circulating glucose levels. We found that primary tumor growth was about 20-fold less in DON treated mice than in untreated control mice. We also found that DON treatment administered alone or in combination with CR inhibited metastasis to liver, lung, and kidney as detected by bioluminescence imaging and histology. Although DON treatment alone did not reduce the incidence of tumor metastasis to spleen compared to the controls (68% controls, 50% DON treatment), DON administered together with CR significantly reduced the incidence of metastasis to the spleen to 27%, indicating a diet/drug synergy. Furthermore, DON toxicity was less in the DON + CR group than in the DON alone group. Less DON was needed to achieve the same level of tumor growth inhibition when administered with CR than administered alone. Finally, survival was greater in the DON + CR group than in the DON group alone further illustrating drug/diet synergy. Our findings provide proof of concept that metabolic therapies targeting both glucose and glutamine metabolism can manage systemic metastatic cancer. (Supported by Boston College REG). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5421.