Dataset Information

Androgen receptor: a potential therapeutic target for glioblastoma.

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.

SUBMITTER: Zalcman N

PROVIDER: S-EPMC5929440 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Androgen receptor: a potential therapeutic target for glioblastoma.

Zalcman Nomi N Canello Tamar T Ovadia Haim H Charbit Hanna H Zelikovitch Bracha B Mordechai Anat A Fellig Yakov Y Rabani Stav S Shahar Tal T Lossos Alexander A Lavon Iris I

Oncotarget 20180413 28

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 t ...[more]

PMID: 29731997

Similar Datasets

Project description:Glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Its prognosis is one of the worst among all cancer types, and it is considered a fatal malignancy, incurable with conventional therapeutic strategies. As the bioactive multifunctional lipid mediator lysophosphatidic acid (LPA) is well recognized to be involved in the tumorigenesis of cancers by acting on G-protein-coupled receptors, LPA receptor (LPAR) antagonists and LPA synthesis inhibitors have been proposed as promising drugs for cancer treatment. Six LPARs, named LPA1-6, are currently recognized. Among them, LPA1 is the dominant LPAR in the CNS and is highly expressed in GBM in combination with the overexpression of autotaxin (ATX), the enzyme (a phosphodiesterase, which is a potent cell motility-stimulating factor) that produces LPA.Invasion is a defining hallmark of GBM. LPA is significantly related to cell adhesion, cell motility, and invasion through the Rho family GTPases Rho and Rac. LPA1 is responsible for LPA-driven cell motility, which is attenuated by LPA4. GBM is among the most vascular human tumors. Although anti-angiogenic therapy (through the inhibition of vascular endothelial growth factor (VEGF)) was established, sufficient results have not been obtained because of the increased invasiveness triggered by anti-angiogenesis. As both ATX and LPA play a significant role in angiogenesis, similar to VEGF, inhibition of the ATX/LPA axis may be beneficial as a two-pronged therapy that includes anti-angiogenic and anti-invasion therapy. Conventional approaches to GBM are predominantly directed at cell proliferation. Recurrent tumors regrow from cells that have invaded brain tissues and are less proliferative, and are thus quite resistant to conventional drugs and radiation, which preferentially kill rapidly proliferating cells. A novel approach that targets this invasive subpopulation of GBM cells may improve the prognosis of GBM. Patients with GBM that contacts the subventricular zone (SVZ) have decreased survival. A putative source of GBM cells is the SVZ, the largest area of neurogenesis in the adult human brain. GBM stem cells in the SVZ that are positive for the neural stem cell surface antigen CD133 are highly tumorigenic and enriched in recurrent GBM. LPA1 expression appears to be increased in these cells. Here, the author reviews research on the ATX/LPAR axis, focusing on GBM and an ATX/LPAR-targeted approach.

Dataset Information

Androgen receptor: a potential therapeutic target for glioblastoma.

Publications

Androgen receptor: a potential therapeutic target for glioblastoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets