Doctor of Philosophy (PhD)
Medical Sciences Interdepartmental Area
Dr. Chi Zhang
Dr. Chi Lin
Glioblastoma (GBM) is the most aggressive primary brain malignancy. The standard treatment of this tumor is surgery, followed by radiation with concurrent and adjuvant temozolomide. GBM cancer stem cells (CSCs) have been proposed to be responsible for radioresistance. It is necessary to identify novel therapeutic agent(s) that can pass the blood-brain barrier (BBB) and enhance radiation effects. Targeting the androgen receptor (AR) is promising in treating glioblastoma (GBM) in cell culture, and flank implant models but the mechanisms remain unclear. AR antagonists, including enzalutamide, are available for treating prostate cancer patients in the clinic and can pass the BBB; thus, they are potentially good candidates for GBM treatment but have not been tested in GBM orthotopically. Our current studies confirmed that most GBM tumors overexpress AR in both genders in patients.
Furthermore, higher AR expression levels are associated with higher-grade disease and histopathologic features predicting poorer prognosis in lower-grade gliomas. We found that enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Although confocal microscopy demonstrated that AR is expressed but not specifically in glioma cancer stem cells (CSCs) (CD133+), enzalutamide treatment significantly decreased the CSC population in cultured monolayer cells and spheroids, suppressed the tumor sphere-forming capacity of GBM cells, and downregulated CSC gene expression at mRNA and protein levels in a dose- and time-dependent manner. For the first time, we have demonstrated that enzalutamide treatment decreased the density of CSCs in vivo and improved survival in an orthotopic GBM mouse model. Furthermore, we found that AR antagonists (ARAs) have a radio-sensitizing effect on GBM cell lines. ARAs induced apoptosis of GBM cells and arrested the cell cycle of GBM cell lines at the G2/M phase. ARAs decreased the DNA repair gene expression level. ARAs suppressed the leukemia inhibitory factor (LIF)-STAT3 pathway and reversed the phosphorylation status of the linker domain (pSmad3L) and c-terminal domain of Smad3 (pSmad3C) thus modulating the signal transduction in the transforming growth factor-β (TGFβ) pathway. ARAs plus RT achieved 100% overall survival in the orthotopic GBM mouse model. Thus we concluded that ARAs plus radiotherapy could be an alternative treatment for GBM.
Zhao, Nan, "Targeting Androgen Receptor on Glioblastoma" (2022). Theses & Dissertations. 646.
Available for download on Saturday, April 27, 2024