Androgen receptor: a potential therapeutic target for glioblastoma
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Nomi Zalcman1,2,*, Tamar Canello1,2,*, Haim Ovadia2, Hanna Charbit1,2, Bracha Zelikovitch1,2, Anat Mordechai1,3, Yakov Fellig4, Stav Rabani5, Tal Shahar5,6, Alexander Lossos1,2,3,** and Iris Lavon1,2,**
1Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
3Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
4Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
5The Laboratory for Molecular Neuro-Oncology, Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, Israel
6Department of Neurosurgery, Shaare Zedek Medical Center, Jerusalem, Israel
*The first two authors contributed equally to the study
**The last two authors contributed equally to the study
Iris Lavon, email: [email protected]
Keywords: androgen receptor (AR); gliomas; AR variant 7 (AR3); AR antagonist; glioblastoma (GBM)
Received: November 15, 2017 Accepted: March 14, 2018 Published: April 13, 2018
The median survival time of patients with glioblastoma is still poor (14.6 month), partly due to a lack of effective treatment.
We have observed that androgen receptor (AR) is amplified in glioblastomas at the DNA, RNA and protein levels. The AR gene was amplified in 27% of glioblastoma specimens from men (n=22) and of 38.2% from women (n=21). AR-RNA was overexpressed (>2.5 fold) in 93% (n=30), and AR-protein was induced (>two fold) in 56% of the glioblastomas samples (n=16). Thirty percent of the glioblastomas (n=21) also expressed a constitutively active AR-splice-variant (AR-V7/AR3) lacking the Ligand-Binding-Domain. Following these findings, we examined the effect of pharmacological inhibition of androgen receptor in vitro and in vivo, as well as of genetic silencing of the receptor in glioblastoma cell lines. AR antagonists, induced concentration-dependent death in three glioblastoma cell lines, as well as in two glioma initiating cell lines. Silencing of AR expression by siRNA induced cell death in the three tested glioblastoma cell lines. Enzalutamide given orally to nude mice bearing subcutaneous human glioma xenografts resulted in a 72% reduction in tumor volume (p=0.0027).
The presence of AR-V7/AR3 in glioblastoma, together with the present data showing that genetic silencing of the full length AR in cell lines and pharmacological inhibition of AR, induce GBM cell death in vivo and in vitro, point to the important role of AR in GBM survival and render a potential therapeutic target for this devastating disease.
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