STEM-03 - Targeting androgen signaling in glioblastoma

Friday, November 17, 2023

7:30 PM – 9:30 PM PT

Location: Exhibit Hall A/B

Poster Presenter(s)

Sofia Mason

Garvan Institute of Medical Research
Darlinghurst, New South Wales, Australia

Author(s)

SC

Sylvia Chung

School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney
Sydney, New South Wales, Australia
BP

Beatriz Perez San Juan

Garvan Institute of Medical Research
Sydney, Australia
Hao-Wen Sim

The Kinghorn Cancer Centre and Chris O'Brien Lifehouse
Sydney, New South Wales, Australia
RD

Rachel Dear

Kinghorn Cancer Center, Darlinghurst, Australia
Darlinghurst, Australia
BD

Bryan W. Day

Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer
Brisbane, Queensland, Australia
JH

Jeff Holst

School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney
Sydney, New South Wales, Australia
CC

Christine Chaffer

Garvan Institute of Medical Research
Sydney, Australia

Background: Glioblastoma is a lethal brain cancer. Androgen receptor (AR) transcript levels and protein expression are upregulated in glioblastoma compared to normal brain. AR signaling has a role in cancer stem cell function in various cancers. Stem cell activity and cancer cell plasticity represent a key resistance mechanism in glioblastoma. Thus, potent brain-penetrant anti-androgen therapies have the potential to improve treatment outcomes in glioblastoma.

Methods: Clinical samples and patient derived xenografts were assessed for AR expression by immunohistochemistry. Cytoplasmic AR+ and AR- glioblastoma patient-derived xenografts maintained under stem cell conditions were tested in vitro for their response to anti-androgen therapies (abiraterone, enzalutamide and seviteronel). Stem cell function was assessed using a tumoursphere assay. Changes in plasticity markers, including ZEB1, were measured with immunofluorescence.

Results: ~55% of people with glioblastoma have detectable cytoplasmic AR based on immunohistochemistry. AR-positive patient-derived glioma stem cell line RN1 was inhibited by low concentrations of anti-androgen agents, with seviteronel having the lowest half maximal inhibitory concentration (IC50) (at 96 hours: enzalutamide 52µM, abiraterone 12µM, seviteronel 7µM). AR-negative line WK1 was also inhibited though with higher IC50s (at 96 hours: enzalutamide 63µM, seviteronel 21µM). Conventional cell lines U87 and U251 were also inhibited by anti-androgen monotherapy. Tumoursphere assays demonstrated that anti-androgen agents inhibit the tumour-forming ability of cells, with seviteronel and abiraterone showing more inhibition than enzalutamide. Immunofluorescence analysis showed downregulation of plasticity marker ZEB1 with anti-androgen treatment (normalised mean fluorescent intensity: abiraterone 0.84, enzalutamide 0.91, seviteronel 0.74).

Conclusions: Glioblastoma is a devastating disease, lacking effective or targeted treatments. Targeting AR with repurposed anti-androgen drugs may be a promising therapeutic strategy, with the potential to abrogate treatment resistance. We are now evaluating these anti-androgen regimens in animal experiments, which will provide a more replicative microenvironment and confirm blood-brain barrier penetrance.