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• Decryption of the leukaemia cell-selective apoptogenic<br />
action of TRAIL. Based on the original fi nding of members<br />
of this consortium that several anti-leukaemogenic<br />
treatments activates the TRAIL death pathway, and the<br />
observation that TRAIL signalling induces apoptosis in<br />
tumour, but not normal cells, the molecular mechanism(s)<br />
underlying this fascinating potential will be defi ned in<br />
suitable cellular models using a plethora of genomic<br />
technologies.<br />
• Therapeutic potential and toxicities of TRAIL in animal<br />
models. Based on regulable TRAIL expression systems,<br />
EPITRON will establish mouse models to assess the<br />
spectrum of anti-cancer activities and possible toxicities<br />
of TRAIL in vivo using both ubiquitous and tissueselective<br />
expression paradigms. At the same time ‘reporter<br />
mice’ will be created, which will allow monitoring activation<br />
of the TRAIL signalling pathway by (epi-)drugs.<br />
• Generation and validation of novel epigenetic drugs.<br />
Crystal structures and innovative chemistry will be used<br />
to generate compounds that (selectively) modulate the<br />
activity of epigenetic enzymes/machineries.<br />
• Models for epigenetic therapy of solid cancers. Among<br />
the several tumour mouse models used by EPITRON,<br />
studies will be performed to assess effi cacy and mechanisms<br />
of HDACi and novel EPITRONgenerated epi-drug<br />
actions in breast cancer models. In these studies, primary<br />
cell cultures derived from the above mouse models (and<br />
their normal counterparts) will also be used. Moreover,<br />
EPITRON will establish as a novel tool matched pairs of<br />
primary normal and cancer cells from the same patients<br />
to assess (epi-)drug action, especially tumourselective<br />
activities. As an example of a gender cancer, primary<br />
patient-matched cultures of normal and breast cancer<br />
epithelial cells will be studied.<br />
Potential applications<br />
In their entirety, the studies performed in AML, breast, skin<br />
and colon cancer preclinical models will provide a framework<br />
for a detailed molecular defi nition of ‘epigenetic<br />
therapy’, which will pave the way to more focused and<br />
appropriate protocols for future clinical trials.<br />
Coordinator<br />
Hinrich Gronemeyer<br />
CERBM-GIE Centre Européen<br />
de Recherche en Biologie<br />
et Médecine – Groupement<br />
d’Intérêt Économique<br />
Illkirch, Strasbourg, France<br />
hg@igbmc.u-strasbg.fr<br />
Partners<br />
Saverio Minucci<br />
Pier Giuseppe Pelicci<br />
Istituto Europeo di Oncologia<br />
Milano, Italy<br />
Henk Stunnenberg<br />
Stichting Katholieke Universiteit<br />
Nijmegen, The Netherlands<br />
Angel De Lera<br />
Universidad de Vigo<br />
Vigo, Spain<br />
Lucia Altucci<br />
Seconda Università<br />
degli Studi di Napoli<br />
Napoli, Italy<br />
Hugues de The<br />
Centre Nationale pour la<br />
Recherche Scientifique<br />
Paris, France<br />
Project number<br />
LSHC-CT-2004-518417<br />
EC contribution<br />
€ 10 904 474<br />
Duration<br />
60 months<br />
Starting date<br />
01/11/2005<br />
Instrument<br />
IP<br />
Project website<br />
www.epitron.eu<br />
Adriana Maggi<br />
Università degli Studi di Milano<br />
Milano, Italy<br />
Tony Kouzarides<br />
University of Cambridge<br />
Cambridge, United Kingdom<br />
Olli Kallioniemi<br />
University of Turku<br />
Turku, Finland<br />
Kurt Berlin<br />
Epigenomics<br />
Berlin, Germany<br />
Tiziana Cataudella<br />
Congenia<br />
Milano, Italy<br />
Holger Hess-Stumpp<br />
Schering AG<br />
Berlin, Germany<br />
Abbie Harris<br />
Abcam<br />
Cambridge, United Kingdom<br />
BIOLOGY 35
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