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.

Targeted RNA NextGenSeq profiling in oncology using single molecule molecular inversion probes

“…Our data confirm expression of the prostate cancer marker PSMA on microvasculature of glioblastoma, possibly providing opportunities for tumor-vascular targeting [55][56][57]. In a recent publication high expression levels of androgen receptor were described in glioblastomas, that actually translated into sensitivity to the AR antagonist enzalutamide [39]. Notably, our data also confirmed the identification of CA12v2 as a marker of poor prognosis in glioblastoma patients [58].…”

“…SmMIPs were designed by an adjusted version of the MIPgen algorithm [37] and were ordered from Integrated DNA Technologies (Leuven, Belgium). The set of smMIP probes used in [34] was expanded with probes for detection of novel transcripts of interest that play a role in a wide variety of cancer types, including prostate cancer markers prostate specific membrane antigen (PSMA [38]) and androgen receptor and its splice variant ARv7 [39] (Table 1). Furthermore, smMIP probes were included for specific detection of splice variants by placing extension and ligation probes on neighboring exons, e.g.…”

<p>Dihydrotestosterone Induces Proliferation, Migration, and Invasion of Human Glioblastoma Cell Lines</p>

“…It has been reported that GBM biopsies overexpress AR, and that its levels are directly correlated to the astrocytomas grade. 13 , 14 , 16 Activation of AR by T induces migration, proliferation, and invasion of human GBM derived cell lines, 18 and in line with this, low levels of androgens are associated with a lower risk of glioma; 13 – 19 Finasteride (FIN) and dutasteride (D), both inhibitors of 5αR, have been proposed for GBM treatment. 20 , 21 Since T promotes GBM progression and it is converted into DHT (a more potent androgen), in this work we evaluated the effects of DHT, FIN, and D on proliferation, migration, and invasion of human GBM derived cell lines.…”

The Role of Translocator Protein TSPO in Hallmarks of Glioblastoma

“…In line with these findings, an increased level of testosterone has been reported in patients with GBM [ 113 ]. In addition, androgen receptors are overexpressed in human GBM, and the genetic silencing of androgen receptors as well as their pharmacological inhibition, induce GBM cell death in vivo and in vitro [ 114 , 115 , 116 ]. Furthermore, the proliferation of GBM-derived cells was increased by testosterone, an effect that was antagonized by the androgen receptor antagonist flutamide [ 113 ].…”