@article{3a6425a727f0456192f0ff7de1636ffb,
title = "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 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.",
author = "Werner, {Christian K.} and Nna, {Uchechi J.} and Hanshi Sun and Kari Wilder-Romans and Joseph Dresser and Kothari, {Ayesha U.} and Weihua Zhou and Yangyang Yao and Arvind Rao and Stefanie Stallard and Carl Koschmann and Tarik Bor and Waldemar Debinski and Hegedus, {Alexander M.} and Morgan, {Meredith A.} and Sriram Venneti and Edwina Baskin-Bey and Spratt, {Daniel E.} and Howard Colman and Sarkaria, {Jann N.} and Chinnaiyan, {Arul M.} and Eisner, {Joel R.} and Corey Speers and Lawrence, {Theodore S.} and Strowd, {Roy E.} and Wahl, {Daniel R.}",
note = "Funding Information: This work was funded by grants from Innocrin Pharmaceuticals, Inc., and the Jones Family Foundation Fund within the Chad Carr Pediatric Brain Tumor Center to D.R. Wahl. D.R. Wahl was also funded by a University of Michigan Funding Information: A. Rao reports grants from Grants (ACS, NIH), other from Voxel Analytics, LLC (consulting) and Agilent Technologies (grant) outside the submitted work. W. Debinski reports personal fees from WPD Pharmaceuticals and VoltMed outside the submitted work; in addition, W. Debinski has a patent for US 6,296,843 issued, a patent for US 6,428,788 issued, a patent for US 6,518,061 issued, a patent for US 6,576,232 issued, US 6,630,576 issued, a patent for US 6,884,581 issued and licensed to Targepeutics, a patent for US 6,884,603 issued, a patent for US 7,338,929 issued, a patent for US 7,960,361 issued, a patent for US 8,343,461 issued, licensed, and with royalties paid from WPD Pharmaceuticals, a patent for US 8,362,207 issued, licensed, and with royalties paid from WPD Pharmaceuticals, a patent for US 8,435,534 issued, a patent for US 9,005,600 issued, licensed, and with royalties paid from WPD Pharmaceuticals, a patent for US 9,290,558 issued, licensed, and with royalties paid from WPD Pharmaceuticals, a patent for US 9,296,785 issued, licensed, and with royalties paid from WPD Pharmaceuticals, a patent for US 9,771,404 issued, a patent for US 9,868,788 issued, licensed, and with royalties paid from WPD Pharmaceuticals, a patent for US 9,878,013 issued, a patent for US 9,974,830 issued, licensed, and with royalties paid from WPD Pharmaceuticals, a patent for US 9,975,942 issued, licensed, and with royalties paid from WPD Pharmaceuticals, a patent for US 10,233,224 issued, licensed, and with royalties paid from WPD Pharmaceuticals, a patent for US 10,519,210 issued, licensed, and with royalties paid from WPD Pharmaceuticals, and a patent for US 10,676,529 issued, licensed, and with royalties paid from WPD Pharmaceuticals. M.A. Morgan reports grants and personal fees from AstraZeneca outside the submitted work. D.E. Spratt reports grants and personal fees from Janssen and AstraZenica outside the submitted work. H. Colman reports personal fees from Innocrin (advisory board) during the conduct of the study; personal fees from Deciphera (advisory board), Karyopharm (advisory board), Newlink Genetics (advisory board), Orbus (advisory board), Private Health (consultant), Best Doctors/ Teledoc (consultant), Bayer (advisory board), and Forma Therapeutics (advisory board) outside the submitted work. J.N. Sarkaria reports grants from Basilea, Sanofi, Beigene, Lilly, Glaxo Smith Kline, Peloton, Glionova, Bristol Myers Squibb, Cavion, Curtana, Forma, AbbVie, Actutate, Boehringer Ingelheim, Bayer, Celgene, Cible, Mitochon, and Wayshine outside the submitted work. J.R. Eisner reports other from Innocrin Pharmaceuticals (employee of Innocrin Pharmaceuticals at the time of the study conduct) outside the submitted work; in addition, J.R. Eisner has a patent for provisional pending (provisional patent covering the role of seviteronel in the treatment of glioblastoma). R.E. Strowd reports grants from NIH, American Society of Clinical Oncology, Southeastern Brain Tumor Foundation, Alpha Omega Alpha, other from Novocure (consulting), Monteris Medical (consulting), American Academy of Neurology (editorial stipend) outside the submitted work. D.R. Wahl reports grants from Innocrin Inc. during the conduct of the study; grants and personal fees from Agios Inc. outside the submitted work; in addition, D.R. Wahl has a patent for the development of biomarkers of treatment response in glioblastoma pending. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = oct,
day = "1",
doi = "10.1158/1535-7163.MCT-20-0095",
language = "English (US)",
volume = "19",
pages = "2163--2174",
journal = "Molecular cancer therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "10",
}