Euregional Pact II

Evaluation of innovative tumortheranostics

The Euregional Pact II project (Homepage) is consolidating the expertises of synergistic working groups belonging to 5 universities in the Rhein-Maas area: Maastricht, Gent, Antwerp, Leuven as well as Aachen.

The mutual aim of the consortium is the accelerated development of innovative tumortherapeutics and –diagnostics. This is possible through the complementation of the working groups’ area of expertises in molecular biology, biotechnology, preclinical tumor models and pathology and will be accomplished within a professional scope as well as through use of their different infrastructures.

Additionally, the collaboration between the universities and the Life Science Industry shall be strengthened. The two interest groups BioFlanders and LifetecZONe serve as a connection to the industries.

Until now, the following potential tumor therapeutics were extensively characterized within the working groups of the consortium: Anti-EGFR-ETA’ and AnnexinA5-ETA’.

Anti-EGFR-ETA’

Anti-EGFR-ETA’ is an immunotoxin containing a scFv-fragment binding specifically to the epidermal growth factor receptor (EGFR), which is overexpressed on a variety of tumor cells (e.g. mamma, pancreas, prostate and ovarial carcinoma cells). As toxic moiety, the construct contains a deletion mutant of the bacterial Pseudomonas aeruginosa toxin Exotoxin A (ETA’), which is already used in different constructs employed in clinical trials. After cell binding and receptor-mediated endocytosis of the immunotoxin, ETA’ exits the endosome and translocates to the cytosol, where it induces cell death through the inhibition of protein biosynthesis and subsequent induction of apoptosis. In former experiments, anti-EGFR-ETA’ was already tested successfully in a disseminated pancreatic carcinoma based mouse model and represents therefore a promising therapeutic for the therapy of EGFR-positive tumors.

Annexin A5 derivatives

The protein Annexin A5 specifically recognizes phosphatidylserine (PS) on the cell surface of apoptotic cells. The exposition of these structures occurs upon a so-called membrane-PS-flip. Herewith, the normally cytosol-facing PS is presented on the cell surface. Many tumor cells have this kind of changed membrane-physiology in common, whereas most of the other living cells do not present PS on their cell surface. That’s why Annexin A5 can be used as a specific binder for tumor cells.

The Euregional Pact II consortium could already show that Annexin A5 is taken up in tumor cells and can be employed as targeted carrier for tumor therapeutics. In order to kill tumor cells effectively, a genetic fusion of Annexin A5 to toxins must be arranged.

The potent and well characterized cytotoxic molecule Pseudomonas aeruginosa Exotoxin A (ETA’) was chosen. The fusion product from both domains (Annexin A5-ETA’) will be constructed independently within the consortium, produced procaryotically, purified and its effect will be evaluated in vitro as well as in vivo with respect to its cytotoxicity as well as side effects.

Within the collaboration, diagnostic, ELISA and radiolabeling based test systems shall be developed in addition to the generation of a potent therapeutic. The most precise prognosis of tumor development in combination with minimal amounts of highly effective therapeutics enables an effective treatment with low side effects, which is thus patient-oriented.