**2.3 PSMA as therapeutic target**

82 Prostate Cancer – Diagnostic and Therapeutic Advances

circulation. Instead of that, PSMA undergoes constitutive internalization, which is about threefold enhanced after antibody binding (Liu et al., 1998). It is therefore suggested that PSMA has transport function and that anti-PSMA antibodies might act as surrogates for a yet unknown ligand. The endocytic pathways of PSMA after antibody binding were specified in a recent study and comprise clathrin-mediated endocytosis, macropinocytosis,

To examine the PSMA expression in the prostate, immunohistochemical analyses were performed. In a study with prostate tissue specimen from 184 patients with prostate cancer, the percentage of PSMA positive stained cells averaged about 69.5% (range 20%-90%) in the benign epithelium, 77.9% (range 30-100%) in high grade prostatic intraepithelial neoplasia (PIN) and was highest in adenocarcinomas with a mean of 80.2% (range 30-100%). In contrast, tumor stroma, urothelium, normal vasculature and, with rare exceptions, basal cells were PSMA negative (Bostwick et al., 1998). Other immunohistochemical studies demonstrated a heterogeneous, weak to moderate staining of normal prostate epithelial cells, and a homogeneous, extensive staining of prostate adenocarcinomas and metastases

PSMA expression is highly organ specific. An extraprostatic expression was only detected in secretory cells of the salivary glands (Israeli et al., 1994; Troyer et al., 1995; Wolf et al., 2010a), in cryptic cells of the duodenal brush border (Chang et al., 1999; Wolf et al., 2010a), and in a subset of proximal renal tubules (Liu et al., 1997; Silver et al., 1997; Chang et al., 1999). In some studies, an additional expression was found in the brain and in the colon, but these results are controversially discussed (Troyer et al., 1995; Silver et al., 1997; Chang et al., 1999; Sacha et al., 2007). Nonetheless, potential side effects of anti-PSMA therapeutics

Interestingly, PSMA is also discussed as an unique anti-angiogenetic target, since it is expressed in the neovascularization of numerous solid tumors (bladder, kidney, breast, pancreas, lung, melanoma), but not in normal blood vessels (Liu et al., 1997; Chang et al., 1999; Chang et al., 2001; Baccala et al., 2007). In this respect, it was found that PSMA regulates cell invasion and tumor angiogenesis by modulating integrin signal transduction

Generally, prostate carcinoma tissues show a higher PSMA expression and an increased enzymatic activity of PSMA compared with normal prostate and benign prostate hyperplasia (BPH) tissues (Lapidus et al., 2000; Burger et al., 2002). Therefore, the question was raised, if PSMA might serve as a valuable biomarker for the management of

Indeed, in different studies a direct correlation between PSMA expression and the Gleason score, which is used for the staging of prostate cancer, was determined for adenocarcinomas (Su et al., 1995; Kawakami & Nakayama, 1997; Burger et al., 2002). Moreover, an upregulation of PSMA was shown in tumor cells of patients with hormonerefractory prostate cancer (Wright et al., 1996; Kawakami & Nakayama, 1997). In a study with tissue specimen from 136 patients it was demonstrated that PSMA can serve as a prognostic biomarker, because it significantly correlates with adverse prognostic factors, like tumor grade, pathological stage, aneuploidy, and biochemical recurrence, and

and clathrin-, calveolae-independent endocytosis (Liu et al., 2009b).

against PSMA expressing normal organs were not described until today.

therefore independently predicts disease outcome (Ross et al., 2003).

(Silver et al., 1997; Wolf et al., 2010a).

in endothelial cells (Conway et al., 2006).

prostate cancer.

**2.2 PSMA as prognostic and diagnostic biomarker** 

Specific characteristics of PSMA concerning its structure, function and expression make it an ideal candidate as a target antigen for the treatment of advanced prostate cancer. (1) Its high and specific expression on the prostate cancer cell surface and the fact that it is not shed into the circulation allows an effective systemic delivery of PSMA targeting therapeutics. (2) Its high organ specificity leads to a minimal binding of anti-PSMA drugs to normal organs and therefore to a maximal reduction of potential side effects. (3) Its expression at all tumor stages enables a therapeutic intervention at any time of the disease. (4) Its internalization after ligand binding can be used for the targeted delivery of intracellular acting drugs. (5) Its enzymatic activity allows the cleavage of prodrugs to active molecules on the surface of prostate cancer cells.

Many preclinical and clinical studies were performed in the last years, which used PSMA as target antigen. They include radioimmunotherapy, the use of immunotoxins, targeted virotherapy, retargeting of immune cells, PSMA vaccination, prodrug activation, photodynamic therapy, and PSMA targeting nanoparticles.
