Prostate-specific membrane antigen (PSMA, GCPII)
Prostate-specific membrane antigen is a type II transmembrane glycoprotein with zinc-depending enzymatic functions. Because of its different roles it is also known as glutamate carboxypeptidase II (GCPII), N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I), NAAG peptidase, and folate hydrolase 1 (FOLH1). It is encoded by the FOLH1 gene. The protein (in humans) has a 707-amino-acid extracellular portion, 24-amino-acid transmembrane portion, and 19-amino-acid intracellular portion. PSMA is highly glycosylated with oligosaccharides, which are essential for proper protein folding and enzymatic activity (Mesters et al., 2006). PSMA shares homology with the transferrin receptor. The enzymatic functions of PSMA can be inhibited with specific antibodies or small molecule inhibitors; after binding, these are internalized with PSMA by endocytosis (Ghosh and Heston, 2004; Eder et al., 2013).
Prostate-specific membrane antigen is expressed in prostate tissue (epithelium), salivary glands, tubular cells in the kidneys, intestine (especially proximal small intestine), and in the central and peripheral nervous system. In prostate tumours, their metastases, and in neovasculature the PSMA is highly overexpressed, providing a target for imaging and therapy (Sweat et al, 2008; Mannweiler et al., 2009; Haberkorn et al., 2016). Only 5-10% of primary prostate cancer lesions are PSMA-negative (Schwarzenboeck et al., 2017). PSMA expression in neovascular endothelium (also in other than prostate tumours) may be related to cell invasion and angiogenesis (Conway et al., 2006).
PSMA hydrolyses carboxy-terminal glutamate residues (thus the name GCPII); this activity manifests as folate hydrolase in the small intestine (in duodenal brush border cells), freeing folic acid to be used in the body as a vitamin. Mutation of FOLH1 gene may lead to impaired intestinal absorption of folate. PSMA may also play a role in the folate metabolism of the prostate (Pinto et al., 1996; Heston, 1997; Chang, 2004). In kidneys PSMA may participate in folate reabsorption.
PET tracers for PSMA
Monoclonal antibodies, conjugated with DOTA and labelled with 64Cu, have shown promise in PSMA-positive tumour model in mice (Alt et al., 2010). Banerjee et al (2014) compared different chelators and found that CB-TE2A provided better contrast than NOTA, PCTA, Oxo-DO3A or DOTA, probably due to its higher stability. Intact antibodies usually have poor tumour penetration and slow blood-pool clearance, as demonstrated by the SPECT tracer [111In]capromab pendetide.
Development of specific and strongly binding monoclonal antibodies to PSMA is difficult because of the high glycosylation of native PSMA. Capromab pendetide and some other mAbs bind to the portion of PSMA that is not exposed on the outer cell surface, such as 7E11, and thus cannot be used to target viable cells. J591 binds the extracellular domain of PSMA, and has been labelled with 89Zr and 124I for PET imaging and also used in radioimmunotherapy.
Because of the limitations of mAbs, small-molecule PSMA ligands have become the object of interest.
One of most used PET tracers for imaging PSMA expressing tumours is [68Ga]PSMA-HBED-CC ([68Ga]PSMA-11). This tracer binds to the extracellular domain of PSMA and is then assumed to be internalized. Image contrast is better than with [18F]fluoromethylcholine (Afshar-Oromieh et al., 2014). It is used for initial staging and detecting recurrent prostate cancer (Bailey & Piert, 2017).
[18F]DCFBC has potential for detection of metastatic prostate cancer (Cho et al., 2012). Blood clearance is relatively slow, partly due to binding to the circulating form of PSMA. Tracer is mainly excreted via kidneys, leading to high radioactivity concentration in the bladder. The fraction of radioactive metabolites in plasma is very low (Cho et al., 2012).
[18F]PSMA-1007 has shown comparable performance to [68Ga]PSMA-HBED-CC, with reduced urinary excretion (Dietlein et al., 2017; Giesel et al., 2017; Kesch et al., 2017). Good tumour-to-background ratios in primary and recurring prostate cancer can be observed 2-3 h after administration (Giesel et al., 2017 and 2018).
Afshar-Oromieh A, Babich JW, Kratochwil C, Giesel FL, Eisenhut M, Kopka K, Haberkorn U. The rise of PSMA ligands for diagnosis and therapy of prostate cancer. J Nucl Med. 2016b; 57; 10(Suppl 3): 79S-89S. doi: .
Chang SS. Overview of prostate-specific membrane antigen. Rev Urol. 2004; 6: S13-S16.
Cho SY, Gage KL, Mease RC, Senthamizhchelvan S, Holt DP, Jeffrey-Kwanisai A, Endres CJ, Dannals RF, Sgouros G, Lodge M, Eisenberg MA, Rodriguez R, Carducci MA, Rojas C, Slusher BS, Kozikowski AP, Pomper MG. Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J Nucl Med. 2012; 53(12): 1883-1891. doi: 10.2967/jnumed.112.104661.
Denmeade S. Prostate-Specific Membrane Antigen. In: Encyclopedia of Cancer. Springer, 2012, pp 3068-3072. doi: 10.1007/978-3-642-16483-5_4782.
Fendler WP, et al. 68Ga-PSMA PET/CT: Joint EANM and SNMMI procedure guideline for prostate cancer imaging: version 1.0. Eur J Nucl Med Mol Imaging 2017; 44: 1014-1024. doi: 10.1007/s00259-017-3670-z.
Foss CA, Mease RC, Cho SY, Kim HJ, Pomper MG. GCPII imaging and cancer. Curr Med Chem. 2012; 19: 1346-1359. doi: 10.2174/092986712799462612.
Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem. 2004; 91(3): 528-539. doi: 10.1002/jcb.10661.
Heston WDW. Characterization and glutamyl preferring carboxypeptidase function of prostate specific membrane antigen: a novel folate hydrolase. Urology 1997; 49(3A): 104-112. doi: 10.1016/S0090-4295(97)00177-5.
Malaspina S, De Giorgi U, Kemppainen J, Del Sole A, Paganelli G. 68Ga-PSMA-PET: added value and future applications in comparison to the current use of choline-PET and mpMRI in the workup of prostate cancer. Radiol Med. 2018; (in press). doi: 10.1007/s11547-018-0929-9.
Mesters JR, Barinka C, Li W, Tsukamoto T, Majer P, Slusher BS, Konvalinka J, Hilgenfeld R. Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer. EMBO J. 2006; 25(6): 1375-1384. doi: 10.1038/sj.emboj.7600969.
Rojas C, Frazier ST, Flanary J, Slusher BS. Kinetics and inhibition of glutamate carboxypeptidase II using a microplate assay. Anal Biochem. 2002; 310: 50-54.
Tewari A (ed.): Prostate Cancer: A Comprehensive Perspective. Springer, 2013. ISBN 978-1-4471-2863-2. doi: 10.1007/978-1-4471-2864-9.
Wolf P. Anti-PSMA antibody-drug conjugates and immunotoxins. In: Phillips GL (ed.) Antibody-Drug Conjugates and Immunotoxins: From Pre-Clinical Development to Therapeutic Applications, Cancer Drug Discovery and Development. Springer, 2013.
Updated at: 2018-11-12
Created at: 2015-03-25
Written by: Vesa Oikonen, Anne Roivainen