Targeted Toxins for the Treatment of Prostate Cancer

Prostate cancer is the second most common cancer and the fifth leading cause of cancer deaths worldwide. Despite improvements in diagnosis and treatment, new treatment options are urgently needed for advanced stages of the disease. Targeted toxins are chemical conjugates or fully recombinant proteins consisting of a binding domain directed against a target antigen on the surface of cancer cells and a toxin domain, which is transported into the cell for the induction of apoptosis. In the last decades, targeted toxins against prostate cancer have been developed. Several challenges, however, became apparent that prevented their direct clinical use. They comprise immunogenicity, low target antigen binding, endosomal entrapment, and lysosomal/proteasomal degradation of the targeted toxins. Moreover, their efficacy is impaired by prostate tumors, which are marked by a dense microenvironment, low target antigen expression, and apoptosis resistance. In this review, current findings in the development of targeted toxins against prostate cancer in view of effective targeting, reduction of immunogenicity, improvement of intracellular trafficking, and overcoming apoptosis resistance are discussed. There are promising approaches that should lead to the clinical use of targeted toxins as therapeutic alternatives for advanced prostate cancer in the future.

Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer

The epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand EGF as binding domain and PE40, the natural toxin domain of Pseudomonas Exotoxin A, or PE24mut, the de-immunized variant thereof, as toxin domains. Both targeted toxins were expressed in the periplasm of E.coli and evoked an inhibition of protein biosynthesis in EGFR-expressing PCa cells. Concentration- and time-dependent killing of PCa cells was found with IC50 values after 48 and 72 h in the low nanomolar or picomolar range based on the induction of apoptosis. EGF-PE24mut was found to be about 11- to 120-fold less toxic than EGF-PE40. Both targeted toxins were more than 600 to 140,000-fold more cytotoxic than the EGFR inhibitor erlotinib. Due to their high and specific cytotoxicity, the EGF-based targeted toxins EGF-PE40 and EGF-PE24mut represent promising candidates for the future treatment of PCa.

Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors

Ligand-targeted toxins (LTTs) are bioengineered molecules which are composed of a targeting component linked to a toxin that induces cell death once the LTT binds its target. Bispecific targeting allows for the simultaneous targeting of two receptors. In this review, we mostly focus on the epidermal growth factor receptor (EGFR) as a target. We discuss the development and testing of a bispecific LTT targeting EGFR and urokinase-type plasminogen activator receptor (uPAR) as two attractive targets implicated in tumor growth and in the regulation of the tumor microvasculature in solid tumors. In vitro and mouse xenograft studies have shown that EGFR-targeted bispecific angiotoxin (eBAT) is effective against human solid tumors. Canine studies have shown that eBAT is both safe and effective against canine hemangiosarcoma, which is physiologically similar to human angiosarcoma. Finding the appropriate dosing strategy and sequencing of eBAT administration, in combination with other therapeutics, are among important factors for future directions. Together, the data indicate that eBAT targets cancer stem cells, it may have a role in inhibiting human tumor vasculature, and its bispecific conformation may have a role in reducing toxicity in comparative oncologic trials in dogs.

Dianthin and Its Potential in Targeted Tumor Therapies

Dianthin enzymes belong to ribosome-inactivating proteins (RIPs) of type 1, i.e., they only consist of a catalytic domain and do not have a cell binding moiety. Dianthin-30 is very similar to saporin-S3 and saporin-S6, two RIPs often used to design targeted toxins for tumor therapy and already tested in some clinical trials. Nevertheless, dianthin enzymes also exhibit differences to saporin with regard to structure, efficacy, toxicity, immunogenicity and production by heterologous expression. Some of the distinctions might make dianthin more suitable for targeted tumor therapies than other RIPs. The present review provides an overview of the history of dianthin discovery and illuminates its structure, function and role in targeted toxins. It further discusses the option to increase the efficacy of dianthin by endosomal escape enhancers.