glutamate carboxypeptidase II

Overview

Glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA), is a type II transmembrane glycoprotein that plays a crucial role in the metabolism of glutamate and is highly expressed in prostate cancer tissues. It functions as a carboxypeptidase, hydrolyzing the C-terminal glutamate residues from Peptides and proteins, which is significant in various physiological processes, including neurotransmission and tumor progression. Due to its overexpression in prostate cancer, GCPII has emerged as a prominent target for diagnostic imaging and therapeutic strategies, particularly in the context of metastatic castration-resistant prostate cancer (mCRPC).

Focus of Latest Publications

Recent publications demonstrate that glutamate carboxypeptidase II (PSMA) remains a pivotal target for both diagnostic imaging and therapeutic intervention in metastatic castration-resistant prostate cancer. Radioligand therapy with 177Lu-PSMA-617 continues to establish itself as a transformative treatment modality, with emerging evidence supporting exploration of alternative radionuclides such as 161Tb and 131I-labeled variants to enhance therapeutic efficacy and overcome resistance in patients with progression following initial therapy. Complementary diagnostic imaging strategies, including 68Ga-PSMA-11 and 68Ga-PSMA-based PET-CT, have proven effective in detecting clinically significant disease in patients with high clinical suspicion but equivocal multiparametric MRI findings, reducing unnecessary biopsy procedures. The expanding repertoire of radiopharmaceutical approaches reflects ongoing chemical optimization, with recent reports demonstrating that conjugation of PSMA ligands with lipid-engineered scaffolds or absorption enhancers like SNAC yields improved tumor uptake and retention while maintaining acceptable kidney clearance profiles.

Combination therapeutic strategies incorporating PSMA-targeted agents are gaining traction, with studies evaluating radioligand therapy combined with androgen receptor pathway inhibitors such as enzalutamide or in concert with novel immune modulation strategies targeting immune tolerance pathways. PSMA-positive circulating tumor cells and extracellular vesicles have emerged as candidate biomarkers associated with treatment response and survival outcomes, enabling liquid biopsy-based patient stratification and real-time monitoring of therapy efficacy. These liquid biopsy approaches reveal that baseline levels of PSMA-positive extracellular vesicle proteins correlate with tumor burden on imaging and serum biomarkers, potentially guiding dosing decisions and identifying patients at higher risk of progression.

Beyond prostate cancer, PSMA-targeted radiopharmaceutical therapy is being investigated in clear cell renal cell carcinoma, where PSMA expression in tumor neovasculature offers a tractable therapeutic target for patients whose disease has progressed after immune checkpoint inhibitor and tyrosine kinase inhibitor therapy. Emerging diagnostic innovations include wash-free digital plasmonic assays capable of detecting PSMA-positive extracellular vesicles in plasma within one hour and electrochemical aptasensors enabling urinary PSMA detection with high sensitivity, positioning PSMA as a non-invasive diagnostic biomarker complementary to conventional imaging modalities. Collectively, these advances underscore PSMA's evolving role in precision oncology, with integrated diagnostic imaging, biomarker-driven patient selection, and rationally engineered radioligand designs enhancing both patient outcomes and therapeutic feasibility across multiple cancer types.

Key Publications

• NEWJun The DARO-flare trial: evaluating the impact of darolutamide on prostate-specific membrane antigen (PSMA) flare and its implications for imaging and staging of hormone-sensitive prostate cancer - study protocol. (BMJ open, 2026, PMID 42315278): "Among these, the prostate-specific membrane antigen (PSMA) has emerged as a pivotal biomarker and therapeutic target in PCa."
• NEWJun Triphosgene-free solid-phase synthesis of urea-containing PSMA-targeting peptides for radiotheranostics: a comparative study. (Organic & biomolecular chemistry, 2026, PMID 42300211): "Prostate-specific membrane antigen (PSMA) is a validated target for prostate cancer imaging and radiotherapy, with most high-affinity ligands incorporating the lysine-urea-glutamate (KuE) pharmacophore."
• NEWJun Effect of [68Ga]Ga-PSMA-11 PET-CT in the diagnosis of prostate cancer in men with equivocal or clinically high-risk non-suspicious findings on multiparametric MRI (PRIMARY2): a multicentre, non-inferiority, phase 3, randomised controlled trial. (The Lancet. Oncology, 2026, PMID 42269655): "We aimed to investigate whether gallium-68 ([68Ga]Ga)-prostate-specific membrane antigen (PSMA)-11 PET-CT could reduce the number of people requiring prostate biopsy and limit biopsy to targeted cores, without compromising clinically significant prostate cancer diagnosis."
• May Theranostic Study of PSMA-Targeted Radioligands Modified with Enhancer SNAC. (Journal of medicinal chemistry, 2026, PMID 42126983): "PSMA is an attractive theranostic target for prostate cancer (PCa)."
• May LGALS9 blockade augments vaccine-induced immune responses against prostate cancer. (Journal for immunotherapy of cancer, 2026, PMID 42103355): "Prostate-specific membrane antigen (PSMA)-based vaccination represents a promising immunotherapeutic strategy for prostate cancer; however, its efficacy remains constrained by tumor-induced immune evasion and insufficient activation of antigen-presenting cells."
• Jun Outcome and Safety of Radioligand Therapy With [ 161 Tb]Tb-PSMA-617 After Re-Progression in mCRPC Patients Previously Treated With [ 177 Lu]Lu-PSMA-617. (Clinical nuclear medicine, 2026, PMID 42080618): "To enhance the effectiveness of radioligand therapy (RLT), new prostate-specific membrane antigen (PSMA) targeting radiopharmaceuticals utilizing alternative radionuclides are under active investigation."
• May Liquid Biopsy Biomarkers in Patients With Metastatic Castration-Resistant Prostate Cancer Receiving Prostate-Specific Membrane Antigen Radioligand Therapy: Protocol for a Prospective, Longitudinal Multicenter Observational Study. (JMIR research protocols, 2026, PMID 42054640): "Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) has emerged as a theranostic strategy for metastatic castration-resistant prostate cancer (mCRPC),"
• May Development of Lipid-Engineered PSMA-Targeted Radioligands with Quinoline Scaffold. (Journal of medicinal chemistry, 2026, PMID 42017493): "Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer, making it an effective diagnostic biomarker and therapeutic target for PCa."
• Apr PET Imaging of Accessible Prostate-Specific Membrane Antigen Reveals Dose-Dependent and Tumor Burden-Driven Variability. (Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2026, PMID 42020145): "Prostate-specific membrane antigen (PSMA) is an attractive target for detection and treatment of prostate cancer because of its high, selective expression in tumors."
• May Wash-Free Digital Detection of Tumor Extracellular Vesicles via Plasmonic Droplet Microfluidics. (ACS sensors, 2026, PMID 42011810): "Plasma (10 μL) is coencapsulated with Ab-AuNPs targeting CD9, EpCAM, PSA, PSMA, and PD-L1 in picoliter droplets."