Direct Androgen Receptor Antagonism Enhances Therapeutic PSMA Radioligand Uptake in Prostate Cancer Models

Area of Science:

• Oncology
• Radiochemistry
• Molecular Imaging

Background:

• Prostate-specific membrane antigen (PSMA) is a key target in prostate cancer theranostics.
• Androgen receptor (AR) signaling influences PSMA expression, but its impact on radioligand uptake under different inhibition strategies is not fully understood.

Purpose of the Study:

• To investigate how different methods of inhibiting the AR pathway affect functional PSMA expression and radioligand uptake in prostate cancer models.
• To determine if AR pathway inhibition enhances the efficacy of PSMA-targeted theranostics.

Main Methods:

• AR-positive and AR-negative prostate cancer cell lines were treated with direct AR antagonists (enzalutamide, apalutamide) or an androgen biosynthesis inhibitor (abiraterone).
• PSMA surface expression was measured by flow cytometry.
• Functional uptake of radioligands ([18F]PSMA-1007 and [177Lu]Lu-PSMA I&T) was assessed by gamma counting.
• Glucose metabolism and PSA secretion were evaluated as secondary readouts.

Main Results:

• Direct AR antagonism significantly increased PSMA surface expression and [177Lu]Lu-PSMA I&T uptake in AR-positive models, especially in castration-resistant cells.
• Abiraterone did not consistently enhance radioligand accumulation.
• AR-negative cells showed no significant changes in PSMA or radioligand uptake after AR antagonist treatment.
• [18F]FDG uptake decreased under AR inhibition, indicating enhanced PSMA uptake was not due to global metabolic increase.

Conclusions:

• Direct AR antagonism enhances functional PSMA availability and short-term radioligand uptake in AR-positive prostate cancer.
• These findings support AR-mediated modulation of PSMA-targeted radioligand delivery for theranostic applications.
• Further translational studies are warranted to explore this approach in clinical settings.