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

Christian K Werner1, Uchechi J Nna1, Hanshi Sun1

  • 1Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Molecular Cancer Therapeutics
|August 16, 2020
PubMed

Insights

Androgen receptor (AR) signaling contributes to therapy resistance in glioblastoma (GBM). Targeting AR with antiandrogens may improve radiation therapy effectiveness for AR-positive GBM patients.

Area of Science:

  • Neuro-oncology
  • Molecular biology
  • Endocrinology

Background:

  • Glioblastoma (GBM) presents significant therapeutic challenges due to intrinsic resistance.
  • GBM exhibits sexual dimorphism and expresses steroid hormone receptors, including the androgen receptor (AR).
  • AR signaling is implicated in therapy resistance in other cancers, such as prostate and breast cancer.

Purpose of the Study:

  • To investigate the role of androgen receptor (AR) signaling in glioblastoma (GBM) therapy resistance.
  • To determine if targeting AR with antiandrogens can overcome resistance and enhance radiosensitivity in GBM.

Main Methods:

  • AR expression was assessed in GBM cell lines, patient-derived xenografts (PDX), and human tumors at transcript and protein levels.
  • Gene expression datasets were analyzed to compare AR levels in GBM and normal brain tissue.
  • The effects of antiandrogens on GBM cell line and PDX growth and radiosensitivity were evaluated in vitro and in vivo.
  • Mechanisms of antiandrogen action, including effects on adaptive transcriptional programs and DNA repair post-radiation, were investigated.

Main Results:

  • Nearly half of tested GBM cell lines, PDXs, and human tumors expressed AR, with levels comparable to prostate cancer.
  • AR expression was significantly higher in GBM patient samples than in normal brain tissue.
  • Clinical-grade antiandrogens inhibited growth and enhanced radiosensitivity of AR-positive GBM models.
  • Antiandrogens disrupted adaptive transcriptional responses to radiation and impeded DNA damage repair in AR-positive GBM.

Conclusions:

  • Androgen receptor (AR) signaling is a potential mediator of therapy resistance in glioblastoma (GBM).
  • Targeting AR with antiandrogens shows promise for overcoming resistance and improving outcomes in AR-positive GBM.
  • Combining antiandrogens with radiation therapy may represent a novel therapeutic strategy for AR-positive GBM patients.

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