All ETDs from UAB

Advisory Committee Chair

Anita B Hjelmeland

Advisory Committee Members

Susan Bellis

Douglas Hurst

Louis Burt Nabors

Christopher Willey

Karina Yoon

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glioblastoma (GBM) is the most common adult primary malignant brain tumor with a median survival of about 15 months, even after aggressive treatment. Treatment of GBM is difficult for multiple reasons including the location of the tumor, tumor invasiveness, and the high degree of both inter-and intra-tumoral heterogeneity. Contributing to intratumoral heterogeneity are highly tumorigenic, stem-like tumor cells, with the capacity to self-renew and propagate the tumor, termed brain tumor initiating cells (BTICs). BTICs are also commonly therapy resistant, highly invasive, and metabolically plastic with elevated expression of glucose transporter 3 (GLUT3) allowing them to preferentially survive in low nutrient microenvironments. GLUT3 correlated with poor patient prognosis in GBM, a segregation not seen with GLUT1, another glucose transporter isoform highly expressed in cancers. Data from the literature indicated that GLUT3 correlated with metastasis in several solid tumors and we found elevated GLUT3 expression at the GBM invasive edge. We therefore investigated the role of GLUT3 in invasion using overexpression as a model system. Overexpression of GLUT3 promoted GBM PDX invasion both in vitro and in vivo, a phenotype not seen with GLUT1 overexpression. Generating chimeric proteins in which regions of low homology between GLUT1 and GLUT3 were swapped, we demonstrated a role for the C-terminus in the pro-invasive GLUT3 phenotype. Considering the importance of GLUTs in the glycolytic shift of GBM cells, the restricted expression of GLUT3 in non-tumor tissues, the role of GLUT3 in BTIC survival and the correlation of GLUT3 with poor patient prognosis, GLUT3 is a promising target for novel anti-GBM therapy development. Using structure based virtual screening we predicted compounds likely to bind GLUT3 that were then assessed for their ability to inhibit both glucose uptake and growth of GBM cells derived from human xenografts. From the first screen, two compounds were identified as leads with the ability to decrease glucose uptake and GBM growth. We then performed a second screen which identified improved compounds with an IC50¬ of 300-500 nM, but additional studies are needed to improve the efficacy, stability, solubility, and specificity of these compounds so they could ultimately be moved toward the clinic.

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