Presentation Authors: Benedikt Kranzbühler*, Souzan Salemi, Zurich, Switzerland, Christoph A. Umbricht, Cristina Müller, Villigen, Switzerland, Tullio Sulser, Irene A. Burger, Daniel Eberli, Zurich, Switzerland
Introduction: Lutetium-177-Labeled prostate-specific membrane antigen (177Lu-PSMA-617) therapy is increasingly used in patients with advanced metastatic castration-resistant prostate cancer. However, limitations are a low PSMA surface expression in certain patients. We have previously shown that high doses of dutasteride, a 5-alpha-reductase inhibitor generally used for the treatment of benign prostatic enlargement, alter the PSMA expression in vitro. Using dutasteride in patients might increase the response to therapy via upregulation of PSMA expression. Therefore, we further analyzed the dose and time dependent effects of dutasteride in vitro.
Methods: Androgen receptor expressing prostate cancer cells (LNCaP) were treated for 7 to 14 days with vehicle control (0.1% DMSO) or different concentrations of dutasteride (0.25Î¼M, 0.5Î¼M, 1Î¼M, 5Î¼M). PSMA surface expression was assessed using flow cytometry (FACS) and immunocytochemistry. Total PSMA expression was analyzed by immunoblotting (WES). In addition, uptake and internalization assays of 177Lu-PSMA-617 were performed.
Results: Dutasteride treatment resulted in a significant upregulation of PSMA surface expression compared to vehicle control (0.1% DMSO) after 7 days in all tested concentrations (0.25Î¼M: 155%, 0.5Î¼M: 168%, 1Î¼M: 218%, 5Î¼M: 213%: all p < 0.0001). After 14 days a further, dose dependent increase of PSMA surface expression was detectable (0.25Î¼M: 156%: p < 0.05, 0.5Î¼M: 202%, 1Î¼M: 317%, 5Î¼M: 461%: all p < 0.0001). Total PSMA protein expression was significantly increased after treatment of cells with high concentrations of dutasteride using 5Î¼M for 7 (330%: p < 0.05) or 14 days (330%: p < 0.05), whereas lower concentration did not alter total PSMA expression compared to vehicle control. Further analysis revealed a dose dependent increase in uptake and internalization of 177Lu-PSMA-617 after 7 and 14 days. However, a significantly increased uptake was only observed using 5Î¼M (7d: 161%, 14d: 151: all p < 0.05) and 1Î¼M after 14 days (146%: p < 0.05).
Conclusions: Our results show a concentration dependent effect of dutasteride on PSMA expression and uptake of 177Lu-PSMA-617 in vitro. A short-term treatment of patients with dutasteride might increase the effect of 177Lu-PSMA-617 therapy via upregulation of PSMA expression.