PSMA

PSMA, or Prostate-Specific Membrane Antigen, is a type II transmembrane glycoprotein that is highly expressed in normal prostate tissue and is overexpressed in the majority of prostate cancers, particularly metastatic castration-resistant disease. It functions as a glutamate carboxypeptidase II enzyme in some tissues, with roles in folate and polyglutamate metabolism. The precise physiological function of PSMA outside the prostate is not fully understood, but its elevated expression on prostate cancer cells makes it a useful target for diagnostic and therapeutic approaches.

PSMA serves as a target for diagnostic imaging and theranostics. PSMA-targeted imaging uses radiolabeled ligands, commonly gallium-68 or fluorine-18 labeled compounds, to visualize prostate cancer lesions with PET, enabling initial staging, restaging, and treatment planning. The imaging agents typically bind PSMA on the cell surface and are internalized, providing high-contrast images of tumor sites.

In therapy, PSMA ligands are linked to therapeutic radionuclides and deliver targeted radiation to cancer cells. Lutetium-177 labeled PSMA-617 is the most widely studied and used example. Clinical trials have shown that PSMA-targeted radioligand therapy can improve radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer when added to standard care, leading to regulatory approvals in several regions. Side effects commonly include dry mouth, fatigue, nausea, and, less frequently, bone marrow suppression or renal toxicity, necessitating careful patient selection and monitoring.

Limitations include heterogeneous PSMA expression, which can yield PSMA-negative lesions, and potential resistance or progression on therapy. Ongoing research seeks to optimize agents, dosing, combination strategies, and patient selection to broaden effectiveness and safety.