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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS096531-01
Application #
9090447
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fountain, Jane W
Project Start
2016-06-15
Project End
2018-03-31
Budget Start
2016-06-15
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$264,677
Indirect Cost
$52,875
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294