Expression of the Androgen Receptor Governs Radiation Resistance in a Subset of Glioblastomas Vulnerable to Antiandrogen Therapy

Abstract

◥New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, much as it does in AR-positive prostate and breast cancers. We found that nearly half of GBM cell lines, patient-derived xenografts (PDX), and human tumors expressed AR at the transcript and protein level-with expression levels overlapping those of primary prostate cancer. Analysis of gene expression datasets also revealed that AR expression is higher in GBM patient samples than normal brain tissue. Multiple clinical-grade antiandrogens slowed the growth of and radiosensitized ARpositive GBM cell lines and PDXs in vitro and in vivo. Antiandrogens blocked the ability of AR-positive GBM PDXs to engage adaptive transcriptional programs following radiation and slowed the repair of radiation-induced DNA damage. These results suggest that combining blood-brain barrier permeable antiandrogens with radiation may have promise for patients with AR-positive GBMs.

Androgen Receptor, Although Not a Specific Marker For, Is a Novel Target to Suppress Glioma Stem Cells as a Therapeutic Strategy for Glioblastoma

“…However, there is much less information available in brain tumors for steroid hormone receptor expressions or response to hormonal-particularly androgensuppression. Previous studies, as well as our own, showed that androgen receptors were consistently detected in a higher proportion of gliomas (17,27,28,31). These findings may help to explain the gender difference in GBM incidence and indicate that AR might be a promising therapeutic target for treating GBM.…”

“…It is also noted that the survival curve after enzalutamide treatment showed initially the same pattern as control group but separated eventually indicating a heterogeneity of tumor response to the drug. Our pre-clinical results indicate that likely further dose escalation study for GBM patients or combining this drug with other standard care modalities for GBM such as temozolomide and/or RT may be necessary to further improve the outcome, as supported by the most recently published data from Werner et al in the flank implant tumor model (31).…”

“…To our knowledge, despite these preliminary expression pattern studies of AR in GBM and its known functions/ signaling in prostate cancer, there has been no reported studies in confirming the therapeutic role of targeting AR in GBM in brain although a previous study from Zalcman et al and a very recent report from Werner et al showed promising results in flank implant models (30,31). Therefore, we used a syngeneic orthotopic mouse model to test the hypothesis that AR suppression using the AR antagonist, enzalutamide, is effective to suppress tumor growth in the brain.…”

Impact of sex in the prevalence and progression of glioblastomas: the role of gonadal steroid hormones

“…Werner and cols determined that AR expression at the transcript and protein levels in LN18, T98G glioblastoma cell lines, patient-derived xenografts (PDX), and human tumors overlapped with the expression of this receptor in primary prostate cancer. These authors also found that anti-androgens' treatment slowed the growth and increased sensitivity to radiation of LN18, T98G, and U87 cell lines and patient-derived xenografts (in vitro and in vivo) [111]. These results suggest that T is involved in the growth of these tumors, regardless of the tumors' grade, in the progression toward a more proliferative, migratory, and invasive state (see Fig.…”

Biomarkers In Brain Tumors With Focus On Glioblastoma

“…There is no sudden increase in the incidence of gliomas during and after puberty (83) and data on the increased risk of glioma due to exposure to exogenous hormones are inconclusive, although they tend to lean towards protective properties of estrogens (84). However, in vitro and in vivo studies indicate that by affecting signaling pathways of sex hormones, we may be able to modulate response to radio-and chemotherapy (85,86). Zhou et al showed that GBM cells overexpressing estrogen receptor β were sensitized to TMZ treatment (85), and Werner et al reported that inhibition of the AR sensitizes GBM cells to radiotherapy (86).…”