Csig-13. Androgen Receptor Is Involved in Glioblastoma and Presents A potential Therapeutic Target

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

doi:10.1093/neuonc/now212.174

Cited by 3 publications

(6 citation statements)

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“…The AR-RNA expression findings were validated in 703 glioblastomas by analysis of several datasets, including the TCGA. Bao et al[ 15 ] confirmed some of our previous results [ 10 ] regarding AR protein expression. No correlation was found between the expression of AR RNA and AR protein.…”

Section: Discussionsupporting

confidence: 83%

“…The findings from our laboratory, some of which were previously presented [ 10 ], show amplification and overexpression of AR in GBM. This led to the present investigation of the effect of pharmacological inhibition of AR in vitro and in the subcutaneous in vivo model, as well as the effect of genetic silencing of the receptor in GBM cell lines.…”

Section: Introductionmentioning

confidence: 53%

“…Amplification of the AR gene was observed (two copies) also in the T98G cell line, derived from the GBM of a male patient, but not in U87MG or A172. The analysis was performed following the observation, made according to an OncoScan FFPE array, of LOH at the chromosomal locus containing the AR gene, accompanied by amplification of the other allele in 4/5 GBM specimens from women [ 10 ] ( Supplementary Figure 1 ). To determine whether this AR gene variation influences AR expression, AR-RNA and protein expression were studied.…”

Section: Resultsmentioning

confidence: 99%

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Androgen receptor: a potential therapeutic target for glioblastoma

et al. 2018

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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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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

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Androgen receptor: a potential therapeutic target for glioblastoma

et al. 2018

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“…It has been demonstrated that the AR is highly expressed in some of the GBM patients and contribute to higher disease accidents in men than in women. ,, Because of the high mutation of ARs in GBM, AR antagonists could not be very effective for the treatment of GBM in this regard. , Abolishing the AR protein in GBM cells has more advantages because both wild-type and mutated ARs could be eliminated by this strategy. − Therefore, we initiated the novel approach to induce AR degradation via inhibition of HSP27 in GBM cells because the AR is a well-documented client protein of HSP27 and its stability is dependent on HSP27.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, the incidence of GBM in men is higher than that in women, which is also associated with men experiencing poorer outcome. , Moreover, there are well-reported cellular, molecular, and imaging alterations that underline these sex differences. , These findings suggest that involvement in sex hormones could play a role in GBM development . To elucidate this sex disparity, studies found that an androgen receptor (AR) is overexpressed in GBM and androgens contribute to the GBM tumor progression. − The overexpression of ARs and the role of androgens in GBM are consistent with the gender-related discrepancy of this disease. Therefore, targeting ARs becomes a novel approach in GBM and an AR inhibitor Seviteronel has been investigated in clinical trials for AR-overexpressed GBM patients .…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule HSP27 Inhibitor Abolishes Androgen Receptors in Glioblastoma

Orahoske

Geldenhuys

et al. 2021

J. Med. Chem.

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Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), and antiandrogen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the antiandrogen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize ARs. Inhibition of HSP27 results in AR degradation regardless of the mutation status of ARs, which makes HSP27 a good target to abolish ARs in GBM. Compound I is a HSP27 inhibitor that significantly induces AR degradation in GBM cells via the proteasomal pathway, and it selectively inhibits AR-overexpressed GBM cell growth with IC50 values around 5 nM. The compound also significantly inhibits in vivo GBM xenograft at 20 mg/kg and does not cause toxicity to mice up to 80 mg/kg. These results suggest that targeting HSP27 to induce AR degradation in GBM is a promising and novel treatment.

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Lead Optimization of Androgen Receptor-HSP27 Disrupting Agents in Glioblastoma

Orahoske

Salem

et al. 2023

J. Med. Chem.

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Glioblastoma (GBM) is the most common malignant brain tumor with poor prognosis under the current standard treatment. It is critical to develop new approaches to selectively battle the disease. GBM sex differences suggest that an androgen receptor (AR) is a potential therapeutic target to treat AR-overexpressed GBM. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein that stabilizes AR. Inhibition of HSP27 leads to AR degradation, indicating that HSP27 inhibitors could suppress AR activity in GBM. We have identified a lead HSP27 inhibitor that could induce AR degradation. Lead optimization resulted with two new derivatives (compounds 4 and 26) showing potent anti-GBM activity and improved drug distribution in comparison to the lead compound. Compounds 4 and 6 exhibit IC 50 s of 35 and 23 nM, respectively, to inhibit cell proliferation and also show significant activity to decrease the tumor growth in vivo.

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Csig-13. Androgen Receptor Is Involved in Glioblastoma and Presents A potential Therapeutic Target

Cited by 3 publications

References 0 publications

Androgen receptor: a potential therapeutic target for glioblastoma

Androgen receptor: a potential therapeutic target for glioblastoma

Small-Molecule HSP27 Inhibitor Abolishes Androgen Receptors in Glioblastoma

Lead Optimization of Androgen Receptor-HSP27 Disrupting Agents in Glioblastoma

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