Abstract 1666: Novel glucose transporter inhibitors decrease glioblastoma growth and glucose uptake

Abstract

Abstract Glioblastoma multiform (GBM) is the most common primary malignant adult brain tumor and one of the deadliest cancers. Patients with GBM typically undergo surgical resection, radiation and chemotherapy with temozolomide. Complete tumor resection is virtually impossible due to tumor location and the highly infiltrative nature of GBM, which leads to disease recurrence near the original tumor site. As such, these patients have a dramatically decreased life expectancy. Therapeutic development to prolong survival has been hampered by a high degree of inter- and intra-tumoral heterogeneity. Contributing to tumor heterogeneity is a subset of highly tumorigenic cells, termed brain tumor initiating cells (BTICs), that are able to self-renew and can be highly invasive and therapy resistant. BTICs are often enriched in perinecrotic regions, a GBM hallmark, where they can survive under nutrient restriction via increased glucose transporter 3 expression (GLUT3). GLUT3 has a 5-fold greater capacity for glucose transport than the other major glucose transporter isoform in the brain, GLUT1, and is typically restricted to neurons, testis, preimplantation embryos, and stem cells. GLUT3 expression is elevated in many solid tumor types, including GBM, and correlates with poor patient prognosis. Previously, we have shown that knockdown of GLUT3 in BTICs significantly inhibits their growth both in vitro and in vivo, indicating GLUT3 is a possible target for therapeutic intervention. Using structure based virtual screening, we have identified novel GLUT inhibitors that preferentially decrease the growth and glucose uptake of BTICs with minimal toxicity to non-malignant cells in vitro. Preliminary in vivo assessment of these compounds has not indicated toxicity. Our goal is to identify a potential new therapeutic option targeting metabolic reprogramming for the treatment of glioblastoma, as well as other tumor types. Citation Format: Catherine J. Libby, Sixue Zhang, Gloria A. Benavides, Yanjie Li, Matthew Redmann, Anh N. Tran, Arphaxad Otamias, Victor Darley-Usmar, Marek Napierala, Jianhua Zhang, Wei Zhang, Anita Hjelmeland. Novel glucose transporter inhibitors decrease glioblastoma growth and glucose uptake [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1666.