Abstract
Targeting androgen receptor (AR) has been shown to be 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 clinic and can pass the blood–brain barrier, thus are potentially good candidates for GBM treatment but have not been tested in GBM orthotopically. Our current studies confirmed that in patients, a majority of GBM tumors overexpress AR in both genders. 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 CSC population in cultured monolayer cells and spheroids, suppressed tumor sphere-forming capacity of GBM cells, and downregulated CSC gene expression at mRNA and protein levels in a dose- and time-dependent manner. We have, for the first time, demonstrated that enzalutamide treatment decreased the density of CSCs in vivo and improved survival in an orthotopic GBM mouse model. We conclude that AR antagonists potently target glioma CSCs in addition to suppressing the overall proliferation of GBM cells as a mechanism supporting their repurposing for clinical applications treating GBM.
Highlights
Glioblastoma (GBM) is the most common type of malignant central nervous system tumor in adult patients in the US accounting for about 50% of them [1]
The presence of specific steroid hormone-binding receptors has been correlated with the clinical outcome and response to hormonal therapy in a number of different neoplasias, including breast, prostate and renal cell carcinoma [57]
As well as our own, showed that androgen receptors were consistently detected in a higher proportion of gliomas [17, 27, 28, 31]
Summary
Glioblastoma (GBM) is the most common type of malignant central nervous system tumor in adult patients in the US accounting for about 50% of them [1]. Even with the extensive efforts of research, current standard care using temozolomide concurrently with brain radiation therapy (RT) after maximal safe surgery only achieves a median survival of fourteen months in the overall patient population, or 22 months in the best prognostic group of patients carrying a hypermethylated MGMT promotor [10, 11] With this universally fatal disease due to its resistance to the standard treatment of RT and chemotherapy, any research advances even small may have a significant impact on survival and provide hope to the thousands of patients who are diagnosed annually with this cancer. Steroid hormone receptors including androgen receptor (AR) are members of a superfamily of ligand-activated transcription factors that are potentially oncogenic in gliomas as has been proposed by other researchers [17, 18] and has been confirmed in prostate cancer [19]
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