Final Report Summary - SFMET (HGF/SF and MET in metastasis)
The growth of tumours at distant sites (metastasis) is the process responsible for over 90 % of cancer deaths and there is considerable need for a better understanding of this process and for new therapies for metastatic cancer. The SFMET project focussed on two proteins, i.e. the growth and motility factor HGF/SF and its membrane receptor MET, that could cause cancer cells to move at a distance from their primary site and thus play an important role in the early stages of metastasis. More specifically, the SMET objectives were to:
1. understand how HGF/SF and MET contributed to the process of tumour invasion and metastasis by addressing two key questions, namely how the conditions of low oxygen tension (hypoxia) typical of growing tumours could cause activation of HGF/SF and MET, and hence metastasis, and how HGF/SF and MET cooperated with two other signalling systems, WNT and the chemokines-chemokine receptors, in promoting invasion and metastasis.
2. to determine crystal structures of the HGF/SF-MET complex and of suitably engineered fragments of HGF/SF, such as NK1, that could compete with the natural MET ligand HGF/SF and thus block HGF/SF-dependent MET signalling in cancer cells.
3. to set the foundations for the development of three new classes of low molecular weight drug-like inhibitors of MET signalling, namely compounds that might bind NK1 or MET or SHP-2, a key downstream effector of HGF/SF and MET.
The project achieved all its initial aims and exceeded the initial work plan and generated additional and valuable information on the structure and function of HGFSF and on rational strategies for inhibiting HGF/SF and MET in cancer.
Hypoxia was demonstrated as being a driving force of tumour invasion and progression and MET proved to be a fundamental mediator of this force. The obtained results also implied that targeting MET with specific pharmacological agents represented a valid therapeutic approach to interfere with tumour invasion and metastasis. Moreover, a valuable mouse model to study the cooperation of WNT, MET and CXCR4 signalling pathways was developed and helped to define a critical role for MaCSC during mammary gland tumourigenesis. It also provided new gene signatures predictive of certain types of breast cancer, where they might guide the choice of rational approaches to therapy.
In addition, several implications emerged from the crystal structure of the HGF/SF-heparin-MET complex. Firstly, the structure showed how MET was activated by the physiological ligand HGF/SF. Secondly, it offered new foundations for the development or optimisation of anti-MET antibodies and low molecular weight compounds with antagonistic activity. New structures were achieved and provided independent confirmation of the NK1 binding site onto MET, defined a structural arrangement of domains present in all truncated fragments of HGF/SF containing at least the first two kringle domains and explained the basis for the antagonistic activity of the NK2-C214S and NK4 proteins.
The binding site of compounds on NK1 and crystal structures of the complexes formed by NK1 and low molecular weight compounds clarified the binding mechanism at atomic level. A similar strategy was adopted for MET binding fragments and in all cases lead compounds were defined and became amenable to lead optimisation experiments via medicinal chemistry. Proof of principle for the compounds' activity in vivo was provided and safe pharmacological and toxicological profiles for the best compound in class were defined.
In summary, the SFMET project produced major advances in structural biology, cancer biology and drug discovery that extended our understanding of cancer and offered the foundation for practical medical progress.
1. understand how HGF/SF and MET contributed to the process of tumour invasion and metastasis by addressing two key questions, namely how the conditions of low oxygen tension (hypoxia) typical of growing tumours could cause activation of HGF/SF and MET, and hence metastasis, and how HGF/SF and MET cooperated with two other signalling systems, WNT and the chemokines-chemokine receptors, in promoting invasion and metastasis.
2. to determine crystal structures of the HGF/SF-MET complex and of suitably engineered fragments of HGF/SF, such as NK1, that could compete with the natural MET ligand HGF/SF and thus block HGF/SF-dependent MET signalling in cancer cells.
3. to set the foundations for the development of three new classes of low molecular weight drug-like inhibitors of MET signalling, namely compounds that might bind NK1 or MET or SHP-2, a key downstream effector of HGF/SF and MET.
The project achieved all its initial aims and exceeded the initial work plan and generated additional and valuable information on the structure and function of HGFSF and on rational strategies for inhibiting HGF/SF and MET in cancer.
Hypoxia was demonstrated as being a driving force of tumour invasion and progression and MET proved to be a fundamental mediator of this force. The obtained results also implied that targeting MET with specific pharmacological agents represented a valid therapeutic approach to interfere with tumour invasion and metastasis. Moreover, a valuable mouse model to study the cooperation of WNT, MET and CXCR4 signalling pathways was developed and helped to define a critical role for MaCSC during mammary gland tumourigenesis. It also provided new gene signatures predictive of certain types of breast cancer, where they might guide the choice of rational approaches to therapy.
In addition, several implications emerged from the crystal structure of the HGF/SF-heparin-MET complex. Firstly, the structure showed how MET was activated by the physiological ligand HGF/SF. Secondly, it offered new foundations for the development or optimisation of anti-MET antibodies and low molecular weight compounds with antagonistic activity. New structures were achieved and provided independent confirmation of the NK1 binding site onto MET, defined a structural arrangement of domains present in all truncated fragments of HGF/SF containing at least the first two kringle domains and explained the basis for the antagonistic activity of the NK2-C214S and NK4 proteins.
The binding site of compounds on NK1 and crystal structures of the complexes formed by NK1 and low molecular weight compounds clarified the binding mechanism at atomic level. A similar strategy was adopted for MET binding fragments and in all cases lead compounds were defined and became amenable to lead optimisation experiments via medicinal chemistry. Proof of principle for the compounds' activity in vivo was provided and safe pharmacological and toxicological profiles for the best compound in class were defined.
In summary, the SFMET project produced major advances in structural biology, cancer biology and drug discovery that extended our understanding of cancer and offered the foundation for practical medical progress.
