Rationale:
Glioblastoma (GBM) is a lethal brain cancer, with a 5-year survival rate <5%. Within GBM, there is a population of more aggressive, multipotent and therapy resistant cells called ‘glioma stem cells’. Androgen receptor (AR) signaling is active in these cells1. Thus, anti-androgen therapies have the potential to eradicate glioma stem cells and improve response to treatment, as seen in our lab's breast cancer work2. We have shown that cytoplasmic AR is a biomarker that predicts prognosis. In GBM, ~55% of patients are cytoplasmic AR positive, suggesting that anti-AR therapy combined with standard-of-care therapy may improve survival outcomes for this biomarker-selected subgroup of GBM.
Design:
Cytoplasmic AR positive and AR negative patient-derived GBM cell lines will be tested for their response to anti-androgen therapies (abiraterone, enzalutamide and seviteronel) alone and in combination with temozolomide chemotherapy. Stem cell function will be assessed using a tumoursphere assay, and by measuring the expression of stem cell surface markers before and after therapy.
Results:
Preliminary data suggests AR antagonists are effective in monotherapy in vitro. Once we establish the best AR inhibitor used in synergy with chemotherapy, we will use this combination in vivo. Using orthotopic patient-derived xenograft models of GBM, we aim to demonstrate that anti-AR therapy plus standard therapy improves survival. Analysing these results alongside explant experiments from our collaborators in a multi-site MRFF Australian Brain Cancer Mission funded project, we will gather the pre-clinical data to justify an Australian investigator-initiated Phase I clinical trial.
Conclusions:
Glioblastoma is a devastating disease, lacking effective or targeted treatments. Targeting AR to eradicate aggressive glioma stem cell populations is a promising therapeutic strategy to improve the efficacy of standard treatments, with the potential to greatly improve outcomes for GBM.