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Functional analysis of novel VEGF receptor 2 ligands for application in tumour imaging and anti-angiogenic therapy

English title Functional analysis of novel VEGF receptor 2 ligands for application in tumour imaging and anti-angiogenic therapy
Applicant Hyde Caroline
Number 147530
Funding scheme Marie Heim-Voegtlin grants
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Molecular Biology
Start/End 01.04.2013 - 31.03.2014
Approved amount 24'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Experimental Cancer Research

Keywords (6)

VEGF; Small protein-like inhibitors; Tumour biology; Pre-clinical tumour therapy; Angiogenesis; VEGF receptor 2

Lay Summary (German)

Lead
Der physiologische Prozess der Angiogenese ist hauptsächlich gesteuert durch die Signalübermittlung durch das Protein Vascular Endothelial Growth Factor (VEGF) welches in Endothelzellen an den zellmembrangebundenen VEGF Rezeptor 2 (VEGFR-2) bindet. Klinische Therapieansätze auf dem Gebiet der Anti-Angiogenese sind jedoch weitgehend ernüchternd, wobei die Bedeutung der Signaltransduktion von VEGFR-2 innerhalb der Tumorepithelzellen noch weitgehend unklar ist.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Aufgrund der ernüchternden Therapieerfolge der anti-angiogenen Behandlungsansätze drängen sich zwei Fragestellungen auf:

1)      Könnte eine spezifischere Ansteuerung des VEGF Rezeptors2  mittels „Targeting“ der extrazellulären Domäne bessere Therapieergebnisse aufweisen?

2)      Inwiefern spielt die autokrine Sekretion von VEGF in Tumorzellen eine Rolle für deren Progression?

Ziel des Forschungsprojektes ist die Herstellung von Antikörper-ähnlichen Peptidmolekülen welche weder die intrazelluläre Tyrosinkinasendomäne noch körpereigenes VEGF anpeilen, jedoch effektive Inhibition der VEGFR-2 Aktivitäten aufweisen. Zusätzlich möchten wir mit Hilfe dieser Peptidmoleküle die Bedeutung der VEGFR-2-Aktivität in Tumorzellen mittels Maustumormodellen gezielter untersuchen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Durch die Herstellung spezifischere Inhibitoren erhoffen wir uns eine anti-angiogene Therapie mit weniger Nebenwirkungen und grösserer Wirksamkeit. Des Weiteren bietet ein besseres Verständnis für die Rolle der VEGFR-2 Signaltransduktion in Tumorwachstum und -progression Möglichkeiten für zukünftige Therapieansätze an.

Direct link to Lay Summary Last update: 25.03.2013

Responsible applicant and co-applicants

Name Institute

Publications

Publication
Finding new partnerships; the function of individual extracellular receptor domains in angiogenic signalling by VEGF receptors
Hyde Caroline CAC, Berger Philipp, Ballmer-Hofer Kurt, Finding new partnerships; the function of individual extracellular receptor domains in angiogenic signalling by VEGF receptors, in Feige Jean-Jacques, Pagès Gilles, Soncin Fabrice (ed.), Springer Verlag, Springer Verlag, Chapter 3.

Collaboration

Group / person Country
Types of collaboration
Molecular Partners AG Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Center for Radiopharmaceutical Sciences, PSI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Institute of Pharmaceutical Sciences, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Signalling and Acquired Resistance to Targeted Cancer Therapeutics Poster Pre-clinical evaluation of novel VEGFR-2 inhibitors for application in live tumour imaging and anti-angiogenic therapy 05.01.2014 Cambridge, Great Britain and Northern Ireland Hyde Caroline;
75th Harden Conference - Receptor Tyrosine Kinase Structure and Function in Mammalian Health and Disease Poster Structure-function studies of VEGF receptors 01.09.2013 Sheffield, Great Britain and Northern Ireland Hyde Caroline;
Pharmacogenomics: from Molecules to Medicine Talk given at a conference Development of new allosteric inhibitors of VEGFR-2 for tumour imaging and therapy 09.07.2013 Engelberg, Switzerland Hyde Caroline;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved


Communication with the public

Communication Title Media Place Year

Associated projects

Number Title Start Funding scheme
130463 Structure/function analysis of VEGF receptors 01.05.2010 Project funding (Div. I-III)
134208 Functional analysis of novel VEGF receptor 2 ligands for application in tumour imaging and anti-angiogenic therapy 01.04.2011 Marie Heim-Voegtlin grants

Abstract

Vascular endothelial growth factor receptors (VEGFRs), in particular VEGFR-2, are hugely involved in the regulation of neo-angiogenesis and aberrant VEGF signalling is implicated in various diseases including tumour growth and metastasis. Regulation of VEGF signalling is controlled by VEGFRs which belong to the receptor tyrosine kinase (RTK) family of membrane-bound receptors. Although it is known that ligand binding to the extracellular domain (ECD) leads to receptor dimerization followed by activation of the intracellular kinase domain, the exact mechanisms underlying kinase activation are still only partially understood. Moreover, it is evident that VEGF-targeted treatments currently available on the market are insufficient and even elicit controversial results.The proposed study serves to bring novel insight into receptor activation in VEGFRs and related RTKs. Furthermore, functional analysis of specifically designed VEGFR-2 ECD ligands with and without structural modifications will be performed for characterization of their potential as antagonists in tumour diagnostics and treatment.
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