Abstract P5-05-03: Targeting hypoxia-induced cancer cell metabolism in breast cancer

Abstract

Abstract Rational: Hypoxia contributes to high tumor grade in human breast cancer and is associated with resistance to radiation and chemotherapy. Hypoxia is generally encountered in perinecrotic regions throughout the heterogeneous tumor microenvironment and may be due to rapid tumor grow, insufficient neovascularization or as a result of antiangiogenic and chemoradiation therapies which cause acute vascular thrombosis. Cancer stem-like cells residing within these hypoxic zones compensate for the low concentration of oxygen through alterations in metabolism that favor aerobic glycolysis and de novo fatty acid synthesis. These metabolic derangements are known to enhance proliferation and survival, although the contributing molecular mechanisms are not fully understood. Here we evaluate a panel of FDA approved azole drugs for alternative use as glycolytic inhibitors with and without the fatty acid synthase (FASN) inhibitor, TBV-3166. TVB-3166 is currently in phase II clinical trials and is the first FASNi approved for human testing. METHODS: IC50 values of single or combined agents were determined by MTT under conditions of normoxia and hypoxia using sister plates of estrogen receptor positive or triple negative breast cancer cells, MCF-7, SKBR3 and MDA-MB-231. RESULTS: Because the combination of Itraconazole and TVB-3166 displayed a synergistic enhancement in cell death at a low nanomolar concentrations in MCF-7 cells, we next assessed the efficacy of these drugs in an in vivo xenograft model of breast cancer. Here, 3.6 million MCF-7 cells were implanted into the right flanks of (n=16) athymic nude mice, which were then randomized by tumor volume into 4 groups. Itraconazole and TVB-3166 were administered at 60 mg/kg daily by oral gavage as single agents or combined throughout the duration of the study. After three weeks, mice treated with combined inhibitors exhibited best response with a statistically significant decrease in tumor volume compared to the vehicle control group. CONCLUSION: Given the significant tumor response to the combination of metabolic inhibitors, further studies that evaluate the radiosensitizing effects under conditions of hypoxia are warranted. By targeting hypoxia-induced metabolic pathways during radiotherapy, we may enhance cancer stem-like cell death to dramatically improve patient outcome. Citation Format: Cavazos DA, Gruslova A, Garcia M, Brenner AJ. Targeting hypoxia-induced cancer cell metabolism in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-05-03.