Androgen receptor blockade and its effect on PSMA-localization in prostate cancer: Implications for radioligand therapy.

Prostate-specific membrane antigen (PSMA) is a key target for radioligand therapy (RLT) in prostate cancer (PCa). However, its subcellular localization is critical, as ligand uptake via PSMA mediated endocytosis influences therapeutic efficacy. This study examines the impact of androgen receptor blockade (ARB) on PSMA membrane trafficking and its modulation by endoplasmic reticulum (ER) stress in PCa cell-lines and tissue samples from ARB pretreated patients. LNCaP and VCaP cells were treated with enzalutamide (0.1-10 µM) for 1-7 days. PSMA localization was assessed via optical sectioning, fluorescence profiling, membrane protein isolation, and Western blotting. ER stress markers BiP and PERK were quantified. To evaluate PSMA targeting and therapeutic response, cellular uptake of [¹ ⁷⁷Lu]Lu-PSMA-Imaging and Therapy (I&T) was quantified via gamma counting, while treatment efficacy was assessed through MTS and Live/Dead-staining. ARB significantly increased PSMA membrane localization, with a maximal effect at 1 µM (7 days) or 10 µM (4 days). Optimized conditions led to a fourfold increase in PSMA uptake in LNCaP and a twofold increase in VCaP. However, prolonged or high dose ARB induced ER stress, evidenced by BiP/PERK upregulation, correlating with reduced PSMA trafficking in vitro and in vivo and diminished [177Lu]Lu-PSMA-I&T uptake in vitro. Optimized ARB-RLT combinations significantly enhanced therapeutic efficacy. These findings highlight ARB's potential to enhance RLT-efficiency by optimizing PSMA membrane localization. Crucially, ER stress markers correlated with PSMA trafficking, suggesting serum-based profiling could enable individualized ARB adjustments. Future studies should validate these biomarkers to establish personalized ARB-RLT strategies for improved clinical outcomes.