Centre Objective
The long term aim of the work of the centre is to pave the way for pharmacological intervention with tumour invasion and metastasis in clinical settings, targeting components of extracellular proteolytic enzyme systems. We wish to link the basic knowledge about the tumour biological functions of extracellular proteolytic enzyme systems to research on new concepts for pharmacological intervention with cancer. To do so, we will develop novel biochemical principles for inhibition of proteases, their receptors, and their inhibitors, based on a detailed knowledge about the three-dimensional structures of these proteins, in combination with novel methods of directed evolution and structure-based drug design. Furthermore, we will couple the use of specific pharmacological agents to a precise mapping of the occurrence of their targets in primary tumours and metastases, using non-invasive imaging methods. Thus, the project is likely to contribute to founding new concepts for pharmacological intervention in cancer.
Specifically, we wish to focus on:
- Development of specific inhibitors targeting selected components of proteolytic systems, by directed evolution and structure-based rational design.
- Design of agents which combine non-specific anti-cancer agents with compounds which target them specifically to primary tumours and metastases by binding to components of extracellular proteolytic enzyme systems.
- Test of the therapeutic efficiency of the developed inhibitors in animal tumour models.
- Use of the developed agents for detection of potential targets in primary tumours and metastases by non-invasive imaging methods, thereby optimising the use of the prognostic information in these enzyme systems.
The proposed project includes research groups, from China and Denmark, with diverse, but complementary expertise. By bringing together the X-ray crystal structure analysis expertise of the Chinese partner Mingdong Huang with the protein chemical and molecular biological expertise of the Danish partners Peter Andreasen, Michael Ploug, and Niels Behrendt, it will be possible to reach a novel structural understanding of extracellular proteolysis. The new structural information, in combination with the expertise in directed evolution and combinatorial chemistry of Jørgen Kjems, Michael Ploug, and Peter Andreasen, will form the basis for development of new types of antagonists, which can be further improved by structure-based rational design and organic synthesis by Mingdong Huang, in an iterative working process. The animal experimentation expertise of Dongxu Liu, Jørgen Kjems, Niels Behrendt and their research groups and the tumour biological knowledge of the entire team will provide an optimal basis for therapeutic testing of the developed agents. Niels Christian Nielsen’s and Andreas Kjær’s expertise in imaging techniques will allow the use of the developed agents for imaging purposes and couple the occurrence of targets to susceptibility to specific antagonists.
The partners in China and Denmark have already demonstrated ability to collaborate. There are also established collaborations between the partners in the individual countries. In addition to their own laboratories, the Chinese and Danish partners will bring in their individual networks of established collaborations in Europe and the US. Briefly, the Chinese-Danish collaboration will bring together an expertise and enthusiasm, which would not be possible with researchers from any other countries.