Abstract 1174: Exploiting glioma stem cell metabolism to abrogate radioresistance in glioblastomas

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and, even with aggressive treatment that includes surgical resection, radiation, and temozolomide administration, prognosis is poor due to tumor recurrence. There is evidence that within GBMs a small number of glioma stem cells (GSCs) exist, which are thought to be radiation resistant and may be capable of repopulating a tumor after treatment. Like most cancers, GBMs largely employ aerobic glycolysis to create ATP, a phenomenon known as the Warburg effect. Experiments have shown that the cellular metabolism of GSCs differs from that of differentiated cells, making them an attractive target for novel therapeutic approaches. Much work has been done to analyze the metabolic profiles of GSCs with the goal of identifying potential therapeutic targets, but little data exists linking metabolic changes to radiation resistance. The purpose of this study is to determine the impact of radiation on the cellular metabolism of GSCs and to identify changes that can be exploited for treatment in conjunction with radiation therapy. To this end, we analyzed three human GSC lines harboring unique sets of genetic mutations that were hypothesized to differentially impact cellular metabolism. Experimental approaches include in vitro examination of metabolic rates and mitochondrial stress of the GSC lines via Seahorse extracellular flux analysis with and without radiation administration as well as analysis of tumor xenografts in mice via 13C MR spectroscopic imaging using hyperpolarized [1-13C] pyruvate as a tracer. Additionally, we are employing genomic and proteomic profiling of the GSC lines both in culture and in vivo to categorize metabolic changes following radiation treatment. We show that the basal metabolic rates of GSC lines with distinctive genetic mutations can be differentiated using Seahorse analysis. This is confirmed in vivo by 13C MR spectroscopic imaging, thus revealing a potential non-invasive diagnostic modality. The underlying mechanism behind these metabolic differences and how this relates to each GSC's response to radiation is currently being examined. We expect that this data will result in the identification of molecular targets within the metabolic pathways of cells that can be exploited with drugs in conjunction with radiation therapy to improve the prognosis and survival of patients presenting with GBMs in the clinic. Citation Format: Elizabeth I. Spehalski, Keita Saito, Tamalee Kramp, Anita Tandle, Barbara Rath, Murali Cherukuri, Kevin Camphausen. Exploiting glioma stem cell metabolism to abrogate radioresistance in glioblastomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1174. doi:10.1158/1538-7445.AM2015-1174