Glioblastomas (GBMs) are one of the most aggressive, deadly cancers due in part to the ability of a subset of tumor cells, called brain tumor initiating cells (BTICs), to resist current treatments and cause tumor recurrence. We and others have identified a perinecrotic niche for BTICs which is associated with reduced levels of glucose and other nutrients. We were the first to find that BTICs were able to survive low glucose conditions due to increased glucose uptake that was associated with elevation of the glucose transporter GLUT3. The ubiquitiously expressed glucose transporter GLUT1 was previously known to play a role in cancer, but our study was the first to determine a functional role for this high affinity glucose transporter in GBM cells. We determined that knockdown of GLUT3 with shRNA decreased BTIC growth, neurosphere formation, and tumorigenic potential in vivo. These phenotypic changes with GLUT3 shRNA correlated with a significant decrease in glucose uptake in these cells even though GLUT1 was still present. As there are no known GLUT3 specific inhibitors and our data suggested strong benefit for GLUT3 inhibition, we initiated a collaborative drug discovery effort. This effort involved structure-based computationa and medicinal chemistry studies and biological evaluations to identify GLUT3 selective inhibitors. We have identified two candidate compounds and will continue to evaluate the efficacy of candidate GLUT3 inhibitors against BTIC growth and maintenance and determine their ability to inhibit glucose uptake in a GLUT3 dependent manner. This study is likely to establish a new therapeutic strategy to improve GBM treatment by altering cellular metabolism to delay tumor recurrence or cure the disease.

Public Health Relevance

Glioblastoma (GBM) is a deadly disease for which there is no cure, but there is promise in targeting a highly tumorigenic subset of GBM cells called brain tumor initiating cells (BTICs). BTICs are located in perinecrotic niches with low nutrient levels, and we found that elevated levels of the glucose transporter GLUT3 are critical for the increased glucose uptake and survival of BTICs. We are now using computational and medicinal chemistry strategies, along with preclinical testing, to identify novel compounds that inhibit GLUT3 and prevent BTIC maintenance to improve GBM treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Fountain, Jane W
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University of Alabama Birmingham
Anatomy/Cell Biology
Schools of Medicine
United States
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Libby, Catherine J; Zhang, Sixue; Benavides, Gloria A et al. (2018) Identification of Compounds That Decrease Glioblastoma Growth and Glucose Uptake in Vitro. ACS Chem Biol 13:2048-2057
Libby, Catherine J; Tran, Anh Nhat; Scott, Sarah E et al. (2018) The pro-tumorigenic effects of metabolic alterations in glioblastoma including brain tumor initiating cells. Biochim Biophys Acta Rev Cancer 1869:175-188
Walker, Kiera; Boyd, Nathaniel H; Anderson, Joshua C et al. (2018) Kinomic profiling of glioblastoma cells reveals PLCG1 as a target in restricted glucose. Biomark Res 6:22
Boyd, Nathaniel H; Walker, Kiera; Fried, Joshua et al. (2017) Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo. JCI Insight 2:
Tran, Anh N; Boyd, Nathaniel H; Walker, Kiera et al. (2017) NOS Expression and NO Function in Glioma and Implications for Patient Therapies. Antioxid Redox Signal 26:986-999
Gilbert, Ashley N; Walker, Kiera; Tran, Anh Nhat et al. (2017) Modeling Physiologic Microenvironments in Three-Dimensional Microtumors Maintains Brain Tumor Initiating Cells. J Cancer Stem Cell Res 5: