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TRK<strong>Cancer</strong><br />
The anoikis suppressor TrkB as a target<br />
for novel anti-cancer agents<br />
Summary<br />
The failure of anti-cancer therapies generally results from<br />
locally intractable invasive growth or from the presence<br />
of metastases refractory to treatment with curative intent.<br />
A novel therapeutic strategy is to develop new anti-cancer<br />
drugs specifi cally targeting the invasive or metastatic phenotype<br />
of tumour cells.<br />
We propose to validate at the pre-clinical level a strategy<br />
that targets the critical mechanism allowing apoptosis evasion<br />
and survival of invasive or metastatic tumour cells.<br />
Anoikis is a process by which a cell detached from its resident<br />
tissue undergoes apoptosis as a result of loss of normal<br />
cell-matrix interactions. Loss of anoikis allows survival of<br />
cancer cells in abnormal micro-environments, such as tissue<br />
compartments invaded by the primary tumour, and the<br />
intravascular compartment, during the metastatic process.<br />
The BDNF receptor TrkB is a potent suppressor of anoikis<br />
and is responsible for apoptosis evasion that occurs in<br />
aggressive human tumours overexpressing TrkB.<br />
The aim of the present proposal is to validate TrkB as a target<br />
for new anti-cancer drugs, aiming to restore anoikis and<br />
thereby destroy the invasive and metastatic cancer cells.<br />
Problem<br />
• Metastasis is a cause of cancer relapse.<br />
• TrkB, as an anoikis suppressor, may favour metastasis,<br />
but the relevance of this target has not been assessed in<br />
relevant cancer models.<br />
• There are no TrkB inhibitors ready for clinical trials.<br />
• Biomarkers of metastasis are lacking.<br />
Aim<br />
• To validate TrkB as a target for anti-metastasis agents by<br />
using human tissue-derived animal models.<br />
• To identify novel TrkB inhibitors.<br />
• To explore mechanisms of action of TrkB inhibitors and<br />
to identify biomarkers of metastasis.<br />
82<br />
Keywords | Metastase | xenografts | tyrosine kinases | biomarkers |<br />
tumour profi ling | siRNA | animal models | drug design |<br />
Expected results<br />
• Novel animal models.<br />
• Novel TrkB inhibitors as potential anti-cancer drugs.<br />
• Novel biomarkers of metastasis.<br />
Potential applications<br />
• Novel anti-cancer agents.<br />
• New diagnostic tools and indices of therapeutic effi cacy.<br />
Coordinator<br />
Pierre Sokoloff<br />
Institut De Recherche Pierre Fabre<br />
Castres Cedex, France<br />
Pierre.sokoloff@pierre-fabre.com<br />
Project number<br />
LSHC-CT-2006-037758<br />
EC contribution<br />
€ 2 368 715<br />
Duration<br />
36 months<br />
Starting date<br />
01/01/2007<br />
Instrument<br />
STREP<br />
Partners<br />
Daniel Peeper<br />
Nederlands Kanker Instituut<br />
Amsterdam, The Netherlands<br />
d.peeper@nki.nl<br />
Julia Schueler<br />
Institute for Experimental<br />
Oncology (Oncotest)<br />
Freiburg, Germany<br />
juliaschueler@arcor.de<br />
Wolter Mooï<br />
Vrije Universiteit Medical Center<br />
Amsterdam, The Netherlands<br />
WJ.Mooi@vumc.nl<br />
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
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