Cancer Research in Switzerland - Krebsliga Schweiz

Zaugg Kathrin | OCS 02009­02­2007 | CHF 195,500.–
Labor für angewandte Radio­Onkologie, UniversitätsSpital Zürich, Zürich
Elucidating the role of the hypoxia-protective gene CPT1C in carcinogenesis
Continuation in the project:
Zaugg Kathrin | KLS 02569­02­2010 | CHF 78,000.–
Labor für angewandte Radio­Onkologie, UniversitätsSpital Zürich, Zürich
Elucidating the role of the hypoxia-protective gene CPT1C (Carnitine Palmitoyl-transferase 1C)
in carcinogenesis
Duration: 01.05.2010 – 01.05.2011
Basic biomedical research
Presentation of completed research projects from July 2008 to December 2010
Ballmer­Hofer Kurt | Structural and functional analysis
of ligand-mediated activation of VEGF receptor 2;
identification and characterization of structural motifs
for the development of new receptor inhibitory drugs
for anti-vascular tumor therapy (OCS 02100­08­2007)
Vascular Endothelial Growth Factors (VEGFs) constitute a
family of proteins that regulate blood and lymphatic vessel
development. Vessel formation and the maintenance
of proper vessel organization are absolutely required for
sustaining organ function in higher organisms. Aberrant
vessel formation is associated with various diseases, such
as arteriosclerosis, retinopathies, lymphoproliferative or
rheumatoid disease, and in tumour growth where newly
formed vessels allow cancer cells to grow more rapidly
and to disseminate into the entire body. Tumour vascularization
is a hallmark of many types of highly aggressive
malignancies, such as breast, colon and stomach cancer.
VEGFs bind to receptors expressed on the surface of cells
and thereby activate their target cells to migrate, proliferate
and ultimately to form new vessels. VEGF binding to
cell surface exposed receptors induces changes in receptor
structure that lead to receptor activation thereby giving
rise to the generation of signals transmitted across the
cell membrane to the intracellular milieu of the cell.
We investigated the molecular mechanism of VEGF receptor
activation with the aim to develop new receptor inhibitors
applicable for the treatment of disease associated
with aberrant vessel formation. Studying the structure of
VEGF receptors and VEGF­receptor complexes, we found
that VEGF binding drastically alters the three­dimensional
structure of the receptor. These structural changes are re­
sponsible for receptor activation and give rise to signals
that promote the formation of new vessels. We investigated
VEGF receptors using electron microscopy, X­ray
crystallography and small angle solution scattering techniques.
The structural and functional information gained
in this project was used to develop a comprehensive molecular
model of receptor function that was essential for
further progress in the development of new receptor antagonists
for future medical applications.
Based on the newly gained insights into the activation
mechanism of VEGF receptors, we developed new antibody­like
molecules to block receptor activation. In a follow
up study we are now investigating the potential of
these new molecular tools to block tumour growth in an
animal model.
Project coordinator
Prof. Dr. Kurt Ballmer­Hofer
Laboratory of Biomolecular Research
Molecular Cell Biology
Paul Scherrer Institut
Bldg. OFLC 102
CH­5232 Villigen­PSI
Phone +41 (0)56 310 41 65
Fax +41 (0)56 310 52 88
kurt.ballmer@psi.ch
63