Expression of the Androgen Receptor Governs Radiation Resistance in a Subset of Glioblastomas Vulnerable to Antiandrogen Therapy
Autor: | Joel R. Eisner, Corey Speers, Uchechi J. Nna, Arul M. Chinnaiyan, Joseph Dresser, Sriram Venneti, Ayesha U. Kothari, Jann N. Sarkaria, Waldemar Debinski, Daniel R. Wahl, Alexander M. Hegedus, Kari Wilder-Romans, Hanshi Sun, Theodore S. Lawrence, Daniel E. Spratt, Yangyang Yao, Meredith A. Morgan, Carl Koschmann, Edwina Baskin-Bey, Arvind Rao, Roy E. Strowd, Weihua Zhou, Stefanie Stallard, Tarik Bor, Howard Colman, Christian K. Werner |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research Antiandrogens medicine.medical_treatment Mice SCID Biology urologic and male genital diseases Article 03 medical and health sciences Prostate cancer Mice 0302 clinical medicine Prostate medicine Animals Humans Antiandrogen Therapy Receptor Androgen Antagonists medicine.disease nervous system diseases Androgen receptor Steroid hormone 030104 developmental biology medicine.anatomical_structure Oncology Cell culture Receptors Androgen 030220 oncology & carcinogenesis Cancer research Female Glioblastoma |
Zdroj: | Mol Cancer Ther |
ISSN: | 1538-8514 |
Popis: | 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 AR-positive 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. |
Databáze: | OpenAIRE |
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