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Projects:

Fields of interest include:

• Development and validation of engineered high-affinity protein antagonists to target protein-protein interactions in oncogenes.
• Advancement of monobodies to deliverable intracellular protein-based cancer therapeutics to hitherto untargetable oncoproteins.
• Identification and targeting of allosteric regulatory mechanisms critical for tyrosine kinase signaling.
• Analysis and perturbation of oncogenic signaling networks using functional proteomics.
• Structure-function analysis of signaling proteins involved in oncogenesis and mechanism-of-action studies of targets anti-cancer drugs.

Main Projects:

Targeting common oncogenes with intracellular monobodies (ERC Consolidator Grant project ONCOINTRABODY)

Oncogenic signalling networks display a remarkable degree of plasticity. Despite only a limited number of alterations in oncogenes and tumour suppressor genes in most tumours, the majority of targeted therapeutics (monoclonal antibodies and small-molecule kinase inhibitors) does not strongly improve the survival of cancer patients and suffers from the rapid development of resistance. The rising number of targeted drugs in clinical use inhibits only a very limited number of protein targets (largely kinases). Consequently, most intracellular non-kinase oncoproteins remain untargeted. We have established the use of small engineered antibody mimics, termed monobodies, to potently and specifically target intracellular protein-protein interactions in cancer cell signaling networks. Expression of monobodies resulted in the inhibition of signalling and oncogenesis mediated by the targeted oncoproteins. We aim at developing monobody binders to key intracellular oncoproteins for which no chemical inhibitors exist and testing their activity in cancer cells. To enable a possible clinical translation of monobody-based therapeutics, methods to deliver monobody proteins into cancer cells will be developed using various approaches. 'Mirror-image' monobodies, composed of D-amino acids, will be developed and tested to increase intracellular and plasma stability and to limit immunogenicity, which, together with the developed delivery systems, are planned to be tested in cancer models. Our goal is to establish monobodies as novel class of intracellular protein-based therapeutics. This endeavour uses state-of-the-art protein engineering techniques to address a central problem in cancer medicine and may provide a ground-breaking new approach to target cancer.