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Androgen receptor: a potential therapeutic target for glioblastoma

2018; Impact Journals LLC; Volume: 9; Issue: 28 Linguagem: Inglês

10.18632/oncotarget.25007

1949-2553

Nomi Zalcman, Tamar Canello, Haim Ovadia, Hanna Charbit, Bracha Zelikovitch, Anat Mordechai, Yakov Fellig, Stav Rabani, Tal Shahar, Alexander Lossos, Iris Lavon,

Glioma Diagnosis and Treatment

// Nomi Zalcman 1, 2, * , Tamar Canello 1, 2, * , Haim Ovadia 2 , Hanna Charbit 1, 2 , Bracha Zelikovitch 1, 2 , Anat Mordechai 1, 3 , Yakov Fellig 4 , Stav Rabani 5 , Tal Shahar 5, 6 , Alexander Lossos 1, 2, 3, ** and Iris Lavon 1, 2, ** 1 Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 2 Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 3 Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 4 Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 5 The Laboratory for Molecular Neuro-Oncology, Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, Israel 6 Department 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 Correspondence to: Iris Lavon, email: IrisL@Hadassah.org.il 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 ABSTRACT 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.