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.
This project focuses on two proteins (HGF/SF and MET) (see Glossary below) that can cause cancer cells to move to a distance from their primary site and thus play an important role in the early stages of metastasis. The project aims to:
- understand how the conditions of low oxygen tension (hypoxia) typical of growing tumours can cause activation of HGF/SF and MET and hence metastasis.
- understand how HGF/SF and MET cooperate with another signalling system. Namely the chemokines and their receptors, in promoting metastasis.
- produce antagonists of the MET receptor by protein engineering or by screening for low molecular weight compounds.
- develop inhibitors of critical effectors of MET, such as SHP-2, as an alternative strategy for inhibiting the MET pathway in cancer.
HGF/SF - a protein that causes proliferation of liver cells (Hepatocyte Growth factor) and dispersal/migration of epithelial cells (Scatter Factor)
MET - the product of the c-Met protooncogene and the receptor for HGF/SF
Main results achieved in the first 18 months of the project
The SFMET project has yielded a string of important results during its first 18 months, including:
Engineered tumour cell lines in which oxygen uptake and utilisation can be controlled (Participant 1)
Compound transgenic mice enabling genetic dissection of the MET and WNT pathways in breast cancer (Participant 2)
Crystals of the ternary complex of HGF/SF-heparin-MET (Participant 3)
Crystals of NK1 variants with antagonistic activity (Participant 4)
Small molecule HGF/SF and MET binders and a full NMR assignment of NK1 for analysis of low molecular weight antagonists with their target proteins (Participant 5)
Potent and specific inhibitors of SHP-2(Participant 6).