Poster Presentation 36th Lorne Cancer Conference 2024

Targeting androgen signaling in glioblastoma: a novel biomarker and therapeutic approach (#214)

Sofia RE Mason 1 2 , Sylvia Chung 3 4 , Beatriz Perez San Juan 1 2 , Rachel Dear 1 5 , Bryan Day 6 7 , Hao-Wen Sim 5 8 9 , Jeff Holst 3 4 , Christine L Chaffer 1 2 5
  1. St Vincent's Clinical School, UNSW, Sydney, NSW, Australia
  2. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  3. School of Medical Sciences and Prince of Wales Clinical School, UNSW, Sydney, NSW, Australia
  4. Adult Cancer Program, Lowy Cancer Research Centre, Sydney, NSW, Australia
  5. Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
  6. University of Queensland, Brisbane, Queensland, Australia
  7. QIMR Berghofer, Brisbane, Australia
  8. Chris O'Brien Lifehouse, Sydney, Australia
  9. NHMRC Clinical Trials Centre, University of Sydney, 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 signalling 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 response to treatment 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. Seviteronel is currently being tested alone and with temozolomide or radiation therapy in an orthotopic murine model, with weekly IVIS monitoring and survival as the primary endpoint.

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 96h: enzalutamide 63µM, seviteronel 21µM). 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). Early IVIS monitoring data from our RN1 orthotopic animal experiment suggests that seviteronel monotherapy slows tumour growth by IVIS compared with control. Seviteronel also improves the efficacy of temozolomide chemotherapy when used in combination based on IVIS measurements. Survival data is immature and will be presented at the conference.

CONCLUSIONS: Glioblastoma is a devastating disease, lacking effective or targeted treatments. Targeting AR with repurposed anti-androgen drugs may be a promising biomarker-directed therapeutic strategy, with the potential to abrogate treatment resistance.