Kailin Yang PhD, Presenter: Nothing to Disclose

William Flavahan, Abstract Co-Author: Nothing to Disclose

Samuel Tay Chao MD, Abstract Co-Author: Nothing to Disclose

Jeremy Rich MD, Abstract Co-Author: Nothing to Disclose

To understand how high-affinity glucose transporter (Glut3) promotes glioblastoma (GBM) radioresistance through maintaining tumorigenic hierarchical growth pattern, and to evaluate the therapeutic efficacy of inhibiting Glut3 to sensitize glioblastoma stem cells (GSCs) to radiation therapy.

Examine the functional importance of Glut3 in tumorigenesis through xenograft mouse model. GSCs expressing Glut3 shRNA or non-targeting control were implanted intracranially into immunocompromised mice. Tumor incidence, volume, and mice median survival were recorded. Define the therapeutic benefits of down-regulating Glut3 on GSCs in conjunction with radiation. Glut3-targeting and control shRNAs were given to patient-derived GSCs in combination with radiation (3Gy). MTT assay was conducted 3 days after radiation to evaluate the effect of Glut3 knockdown. Characterize the expression level of Glut3 in determining GBM patient survival. Based on TCGA database, the predictive value of Glut3 for GBM patient outcome was evaluated by examining the correlation between Glut3 expression level and overall survival.

Glut3 is required for in vivo tumorigenesis of GSCs. In vivo tumor propagation assay with patient-derived GSCs demonstrated that targeting Glut3 using shRNA increased the survival of mice bearing human GBM xenografts relative to non-targeting shRNA (p<0.0004). This result demonstrated the essential role of Glut3 in maintaining GSC function in vivo. Knocking down Glut3 sensitizes GSCs to radiation. Glut3 knockdown significantly decreased GSC survival after radiation compared to control (1.7 fold). This result revealed the function of Glut3 in promoting GSC survival after radiation therapy, consistent with its key role in GSC maintenance. Glut3 expression level correlates with GBM patient survival. To evaluate the role of Glut3 in determining GBM patient survival, we generated Kaplan-Meier survival curves using TCGA dataset. Glut3 expression informed poor prognosis, whereas other glucose transporters (Glut1-3) did not correlate with patient outcome.

Our results demonstrated that Glut3 plays a key role in enforcing GBM cellular hierarchy and promoting radiation resistance.

This study provided scientific rationale to apply anti-glucose metabolism medication as potential adjuvant therapy to eradicate GBM and to develop imaging tools to detect GSCs in patients.

Yang, K, Flavahan, W, Chao, S, Rich, J, Radiosensitization of Glioblastoma Stem Cells by Targeting High-affinity Glucose Uptake.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14011971.html