Consequences of metabolic reprogramming by GLUT3 in GBM

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ABSTRACT Glioblastoma (WHO grade IV astrocytoma; GBM) is the most common and deadly primary malignant brain tumor in adults. Therapy development has been hampered by the heterogeneous nature of GBM. Within GBM, a subset of tumor cells known as brain tumor initiating cells (BTICs) are highly tumorigenic and have some properties of neural stem cells. By co-opting the high affinity neuronal glucose transporter type 3 (GLUT3) brain tumor initiating cells (BTICs) can preferentially survive in low nutrient tumor microenvironments; leading to tumor promotion and progression. GLUT3 expression in many solid tumor types such as GBM, colon cancer, head and neck cancers and ovarian cancer is correlated with poor prognosis and survival. High GLUT3 expression also correlates with metastatic or invasive disease. The relationship between GLUT3 expression and invasion in GBM has not been explored. In this study, we aim to understand the role of metabolic reprogramming by GLUT3 in the invasion of GBM and explore opportunities for the pharmacological targeting of GLUT3 . We have identified novel GLUT3 inhibitors that are able to preferentially inhibit the growth and glucose up take of BTICs with little toxicity to non-neoplastic cells. Through this study, we hope to understand the role of GLUT3 in tumors and to identify a potential new therapeutic option to target metabolic reprogramming for the treatment of GBM.