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Volume 2
     

Targeting signals essential for angiogenesis: Gene therapy to prevent new vessel formation and to induce apoptosis and necrosis of tumour vasculature (anti-tumour angiogenesis)

   
Project

QLK3-2002-02059

Cell factory area

3.1.3

EU Contribution

1,409,700 Euro

Duration

36 months

Type

RS

Starting date

01 November 2002

Keywords
endothelial cell proteins
lipsome technology
recombinant adenovirus technology
ABSTRACT

Angiogenesis, the development of new blood vessels by sprouting, occurs in the adult mainly during wound healing, but is also observed in tumours and ophthalmic or rheumatic diseases. The recruitment of new capillaries by solid tumours is important for the malignant process since the expansion of the tumour absolutely depends on this process and the density of the vessels determines the metastatic potential. We propose here to investigate the signals by which three key proteins of endothelial cells, the cells forming the inner layer of blood vessels, control the proliferation, migration and capillary formation. Essential signalling mechanisms triggered by these proteins will be defined at the molecular level and potential target molecules for inhibition of angiogenesis identified. Making use of the recent developments of gene therapy vectors and liposomes, potential inhibitors of these proteins will be evaluated in tumour angiogenesis models.

OBJECTIVES

The general objective of this project is to select therapeutic genes to block angiogenesis and to induce apoptosis and necrosis in tumour vessels by gene therapy methods.

This includes the following specific objectives:

  1. define key targets in the signaling of the VEGF and Tie receptors and the VE-cadherin leading to angiogenesis and cell survival.
  2. select mutant and natural inhibitors to block angiogenesis in in vitro models.
  3. develop adenovirus and liposome technologies for preferential targeting and expression of genes in tumour vessels.
  4. select therapeutic genes incorporated in the developed viral vectors and lipid-based delivery systems following evaluation in animal tumour models.
DESCRIPTION OF THE WORK

The current proposal intends to select inhibitors for three receptor/ligand systems and their downstream signaling shown to be of relevance for individual steps of novel vessel formation, including proliferation, migration and capillary formation of endothelial cells. The VEGF receptors, Tie receptors and VE-cadherin have been shown to be important for novel vessel formation by in vitro assays and gene knock-out experiments in mice. Multiple evidence supports a role in tumour angiogenesis for all three receptor systems and the intracellular signals generated by them. The ligands for VEGF and Tie receptors are produced by tumour cells, and antibodies to VE-cadherin can inhibit tumour angiogenesis. We propose to construct and select inhibitors for these molecules and their signaling based on our previous studies.

We will define key targets and candidate therapeutic genes for gene therapy approaches. Mutants or natural inhibitors will be first tested by transfection and recombinant adenovirus technology. Selected inhibitors shown to be functional in vitro will then be evaluated in animal tumour models. There is good evidence that interruption of some of the targeted pathways will trigger apoptosis of endothelial cells which should lead to vessel destruction and tumour shrinkage. The best candidate therapeutic genes will then be used in improved adenovirus and liposome delivery systems for preclinical testing of inhibition of tumour growth and induction of tumour shrinkage. The information gathered and the genes and technology developed should provide a potential basis for anti-tumour angiogenesis gene therapy. In addition defined key targets will be useful to design screening assays for pharmacological inhibitors.

DELIVERABLES

The project proposes to obtain following deliverables:

  1. key inhibitors for the VEGFR, Tie receptor, VE-cadherin and downstream signaling will be selected and/or constructed.
  2. improved adenoviral and liposome technology for specific targeting and expression in tumour vessels will be developed.
  3. therapeutic genes and delivery systems for inhibition of tumour angiogenesis and growth will be evaluated.

Through preferential targeting and the use of inhibitors functional mainly in activated angiogenic tumour endothelium we intend to achieve maximal effects on tumour vessels and minimal side-effects on normal endothelium. In summary, these studies should evaluate the feasibility of anti-angiogenesis gene therapy strategies using adenovirus and liposome technologies.

CONSORTIUM
COORDINATOR
 
Erhard Hofer
Department of Vascular Biology and Thrombosis Research
University of Vienna
1235 Vienna, Austria
Tel: +43-1-4277 62553
Fax: +43-1-4277 62550
erhard.hofer@univie.ac.at
 
PARTNERS
 
Kari Alitalo
Molecular/Cancer Biology Laboratory
Haartman Institute
University of Helsinki
00014 Helsinki, Finland
Tel: +358-9-1912-6434
Fax: +358-9-1912 6448
Kari.Alitalo@Helsinki.FI

Elisabetta Dejana
Vascular Biology Laboratory
Mario Negri Institute for
Pharmacological Research
20157 Milano, Italy
Tel: +39-02-390141 421
Fax: +31-50-363 3247
Dejana@irfmn.mnegri.it

Kurt Naujoks
MBT Munich Biotechnology GmbH
82152 Martinsried, Germany
Tel: +49-89-8999 6511
Fax: +49-89-8999 6550
kurt.naujoks@mbiotech.de

Matthias Clauss
Department of Molecular Cell Biology
Max-Planck-Institute for Physiological and Clinical Research
61231 Bad Nauheim, Germany
Tel: +49-60-3270 5269
Fax: +49-60-3272 259
MClauss@alpha.kerckhoff.mpg.de

Hidde Haisma
Department of Therapeutic
Gene Modulation
University Centre for Pharmacy
University of Groningen
9600 AD Groningen, The Netherlands
Tel: +31-50-363 7866
Fax: +31-50-363 3247
h.j.haisma@farm.rug.nl