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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.

Projects:

1. 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.

 2. LOEWE Exploration

Degradobodies - Cell-penetrating monobodies for the degradation of oncogenic transcription processes
How can proteins that lead to the development of cancer be removed from cancer cells? The project ‘Degradobodies - cell-penetrating monobodies for the degradation of oncogenic transcription processes’ is investigating this question. 
Cancer is caused by changes in the genetic material of the cell, so-called oncogenes. As a result, cells divide uncontrollably and tumours develop. 
Since 2000, new drugs that bind to oncogenes and block their signalling have been approved for the treatment of cancer patients.
Over the past ten years, two-armed molecules have been developed that block oncogenes with one arm and initiate their destruction in cancer cells with the second arm. This new approach has not yet led to an approved drug and can only be used for a few oncogenes.
The team in the ‘Degradobodies’ project is trying to solve this problem by using antibody-like proteins, so-called monobodies. These can be developed quickly and cost-effectively against any oncogene. The research group will couple monobodies to a second molecule, which will then initiate the destruction of the oncogene - a potentially groundbreaking new approach that can be used to combat a large number of currently inaccessible oncogenes.

3. The European Treatment and Outcome Study for CML (EUTOS 2022) is a multifaceted scientific project on the treatment of patients with Chronic Myeloid Leukemia ("CML") and the optimization of CML management

The overall objective of this European research collaboration is to gain new scientific insights into CML to further optimize treatment and clinical outcomes for CML patients of major European countries. Within the EUTOS consortium, which is generously supported by Novartis Pharma AG and coordinated by the University Hospital Jena, the Hantschel lab studies the mechanisms of primary and secondary (acquired) resistance to the specific BCR::ABL1 (STAMP) inhibitor asciminib. In particular, we are modelling the structural changes of the BCR::ABL1 protein with distinct mutations and elucidate the biology and signaling of allosteric BCR::ABL1 inhibition with the aim to optimize therapy with asciminib and ATP competing drugs. Through enhanced cooperation among EUTOS scientists, we strive to provide a platform for the expedited evaluation of new treatments, combination and discontinuation strategies with the objective of progressing towards curing CML.