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114<br />
Cell proliferation<br />
and apoptosis<br />
Invasion and<br />
metastasis<br />
Angiogenesis<br />
Expected results<br />
The Biology of the <strong>Cancer</strong> Degradome<br />
Cell<br />
differentiation<br />
The DEGRADOME<br />
Proteases, Inhibitors,<br />
Substrates and Receptors<br />
Recruitment of host cells<br />
(inflammatory cells, fibroblasts)<br />
• The determination of Degradome gene expression patterns<br />
in human tumour cell lines and mouse models.<br />
• A detailed analysis of Degradome gene function using<br />
tumour prone mouse models.<br />
• The analysis of protease inhibitor function in combination<br />
with other therapies.<br />
• Elucidation of the interplay between proteases and other<br />
key molecules of intracellular and intercellular signalling.<br />
• Determination of the regulatory factors that control protease<br />
gene expression in tumours and in the tumour-host<br />
dialogue.<br />
• Characterisation of the cellular expression of Degradome<br />
genes for breast and prostate cancer.<br />
• Development of active site-directed inhibitors of metalloproteinases.<br />
• Development of ligands able to prevent the formation of<br />
protease-substrate, protease-inhibitor, protease-receptor<br />
complexes.<br />
• Production of radiotracers for protease ligands for in vivo<br />
imaging, with transfer to clinical paradigms.<br />
Signal<br />
transduction and<br />
gene expression<br />
Cell adhesion<br />
and migration<br />
Matrix<br />
remodelling<br />
Targets of molecular therapeutics can be found in diff erent<br />
aspects of malignant transformation.<br />
Potential applications<br />
Several major pharmaceutical companies have been involved<br />
in the development of synthetic protease inhibitors for cancer<br />
therapy over the past decade. However, the vast majority<br />
of trials have shown these fi rst generation compounds to<br />
have limited eff ects. What is now clear is that the biological<br />
activities of extracellular proteases, and their roles in normal<br />
and diseased tissues, are much more complex than was<br />
originally envisioned. The original notion of proteases solely<br />
as mediators of pathological tissue destruction is an oversimplifi<br />
cation: in fact, some proteases have functions that<br />
inhibit tumour development and progression, and moreover,<br />
their natural inhibitors (TIMPs, PAIs, etc) can in some instances<br />
enhance tumourigenesis. The identifi cation of protease<br />
targets for the design of novel and specifi c interventions will<br />
off er improvements for health care delivery and patient<br />
management. The knowledge obtained in this project can<br />
also be used to identify cancer susceptibility in otherwise<br />
healthy individuals.<br />
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
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