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Keywords | Angiogenesis | vasculogenesis | blood vessels | tumour | endothelial cells | clinical trials |<br />
microarrays | proteomics molecular targets |<br />
ANGIOTARGETING<br />
Multidisciplinary research to explore<br />
and validate molecular targets<br />
for innovative treatments<br />
Summary<br />
Solid tumour growth depends on the recruitment of new<br />
blood vessels that will provide the cancer cells with nutrients<br />
and oxygen. The ANGIOTARGETING project intends to<br />
fi nd new targets on the tumour vasculature. The project will<br />
then defi ne these targets and develop new therapeutic<br />
strategies towards them.<br />
The apparent limited success in translating angiogenesis<br />
research into the clinic is, in our view, based on the fact that<br />
the research fi eld has been fragmented, and no standardised<br />
tools and models have been identifi ed that reliably<br />
refl ect the complexity of tumour angiogenesis mechanisms<br />
in humans.<br />
ANGIOTARGETING will identify and validate new therapeutic<br />
targets directed towards tumour vascular-matrix<br />
interactions, develop new therapeutic strategies and implement<br />
such strategies in pre- and clinical trials. The project<br />
represents a virtual research institute in Europe and consists<br />
of 14 highly competent research centres within the<br />
fi eld of angiogenesis research. To defi ne and validate new<br />
targets related to the tumour vascular transcriptome and<br />
proteome, the consortium will establish high throughput<br />
functional screening technologies for the identifi cation of<br />
novel secreted factors that regulate endothelial cell growth<br />
and survival. This includes the use of robotic platforms that<br />
will be used to identify cDNAs with specifi c cellular functions.<br />
In this project, basic science, translational research<br />
and clinical activities are strongly integrated, in order to<br />
validate defi ned targets and to develop new therapeutic<br />
principles for clinical implementation.<br />
Problem<br />
The signifi cant role of neovessel formation in health and disease<br />
has been clearly demonstrated during the last decade.<br />
The molecular mechanisms that lead to the establishment of<br />
functional blood vessels are also key factors that regulate<br />
tumour progression. Considerable eff orts have been devoted<br />
to research identifying the mechanisms that regulate the<br />
recruitment of blood vessels to tumours. Under normal<br />
conditions, the establishment of blood vessels is a highly<br />
complex and coordinated biological process.<br />
Targeting non-cancer cells that feed and drain the tumour and<br />
form channels through which tumour cells can disseminate,<br />
rather than targeting the neoplastic cells themselves, represents<br />
an approach to cancer therapy that holds particular<br />
promise because these cells are genetically stable, and therefore<br />
less likely to accumulate mutations that allow them to<br />
develop drug resistance. The fi rst meaningful clinical eff ects<br />
of antiangiogenic therapy in human cancer have recently been<br />
demonstrated. However, in spite of some highly encouraging<br />
results, most angiogenesis inhibitors, reported to suppress<br />
tumour growth in animal models, have thus far failed in human<br />
clinical trials. In our view, this refl ects that no standardised<br />
tools and models have been identifi ed that reliably refl ect the<br />
complexity of tumour angiogenesis mechanisms in humans.<br />
The successful translation of potential angiogenesis inhibitors<br />
to clinical application depends partly on the transfer of expertise<br />
from scientists who are familiar with the biology of<br />
angiogenesis to clinicians, as well as an active feedback from<br />
the clinicians to the scientists.<br />
ANGIOTARGETING aims at the identifi cation and validation<br />
of new therapeutic targets in tumour vasculature, develops<br />
new therapeutic strategies and implement such strategies<br />
in pre- and clinical trials. A strong focus on translational<br />
research and clinical implementation will convert R&D results<br />
into direct public and economic benefi ts.<br />
BIOLOGY 13<br />
Aim<br />
The objective is the identifi cation and validation of new<br />
therapeutic targets directed towards tumour vascularmatrix<br />
interactions.<br />
Expected results<br />
• The project will increase our understanding of how<br />
tumours generate a vascular supply.<br />
• The project will develop new technologies to defi ne<br />
and validate key molecular targets that control tumour<br />
vascularisation and invasion.<br />
• The project will identify potential therapeutic targets<br />
towards the tumour vascular and invasive transcriptome<br />
and proteome.<br />
• The project will develop comprehensive bioinformatics<br />
tools for the analysis of high throughput gene and protein<br />
data from defi ned cell populations within tumours.<br />
• The project will develop state-of-the-art platforms for<br />
preclinical and clinical assessment of newly developed<br />
compounds.<br />
• The project will provide new information on how potential<br />
antivascular therapies shall be evaluated in the clinic.<br />
This includes the development of surrogate markers to<br />
evaluate therapeutic effi cacy.