Cancer Research - Europa

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Coordinator Regis Hugon Commissariat à l’Énergie Atomique Paris, France regis.hugon@cea.fr Partners Albert Blondin Ion Beam Applications SA Louvain-la-Neuve, Belgium albert.blondin@iba.be Rob Kreuger Delft University of Technology and Radiation Technology Interfaculty Reactor Institute Delft, The Netherlands R.Kreuger@TNW.tudelft.nl Emilio Migneco Istituto Nazionale di Fisica Nucleare Catania, Italy direzione@lns.infn.it Hanna Kafrouni Dosisoft S.A. Cachan, France kafrouni@dosisoft.com Pavel Olko Instytut Fizyki Jadrowej PAN Krakow, Poland pawel.olko@ifj.edu.pl Thierry Leroux Eldim S.A. Hérouville Saint-Clair, France Alfred Hogenbirk Nuclear <strong>Research</strong> and Consultancy Group Petten, The Netherlands hogenbirk@nrg-nl.com 216 Marta Bucciolini Università di Firenze Florence, Italy marta@dfc.unifi.it Carlo Greco REM Radioterapia SRL Catania, Italy carlo.greco@ieo.it Onori Sandro Istituto Superiore di Sanità Rome, Italy sandro.onori@iss.it Olivier Haas Coventry University Coventry, United Kingdom o.haas@coventry.ac.uk Alan DuSautoy National Physical Laboratory Teddington, United Kingdom Dimitri Lefkopoulos Institut Gustave Roussy Villejuif, France lefko@igr.fr Jean-Marc Fontbonne Centre National de la Recherche Scientifi que Caen, France fontbonne@lpccaen.in2p3.fr Alain Batalla Centre National François Baclesse Caen, France a.batalla@baclesse.fr Wolfgang Sauerwein Universität Duisburg-Essen Essen, Germany w.sauerwein@uni-essen.de Mark Fisher University of East Anglia Norwich, United Kingdom Gloria Bueno Universidad de Castilla-La Mancha Albacete, Spain gloria.bueno@uclm.es John Mills University Hospitals Coventry and Warwickshire NHS Trust Coventry, United Kingdom jam@walsgrve.demon.co.uk Michael Waligorski Centrum Onkologii Oddzial w Krakowie Krakow, Poland z5waligo@cyf-kr.edu.pl Grégoire Malandain Institut National de Recherche en Informatique et Automatique Sophia-Antipolis, France gregoire.malandain@sophia.inria.fr Francesc Salvat Universitat de Barcelona Barcelona, Spain cesc@ecm.ub.es Sten Larson Scanditronix Wellhöfer AB Uppsala, Sweden Project number LSHC-CT-2004-503564 EC contribution € 7 000 000 Duration 60 months Starting date 01/05/2004 Instrument IP Project website www.maestroresearch.org CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Keywords | Circadian | clocks | cell cycle | cancer | chronotherapeutics | drug delivery | dynamic models | personalized medicine | chronobiology | pharmacology | anticancer drugs | topoisomerase | cyclin dependent kinases | mouse | patients | transcriptome | proteome | phenome | drug development | systems biology | TEMPO Temporal genomics for tailored chronotherapeutics Summary Chronic diseases account for 75 % of the disability-adjusted years in Europe and cause the premature death of 17 million people worldwide. Diff erences in aetiology as well as patient genetic origin, gender, age, lifestyle and biological time structure account for large variability in individual time courses of the same disease entity. Patient-tailored therapeutics is needed to prevent adverse events and improve overall therapeutic activity. Rather than using pharmacogenomics for excluding patients from an active treatment option, TEMPO will combine functional genomics, proteomics, cell signalling, systems biology and pharmacokinetics to optimize therapeutic index in most individual patients. Thus TEMPO will determine 3 to 5 chronotherapeutics schedules with distinct temporal delivery patterns of the same anticancer drug. Each schedule is adjusted to a diff erent dynamic class of temporal genomics and phenomics parameters related to interwoven circadian and cell division cycles and drug metabolism. In vivo, in vitro and in silico approaches are integrated through the multidisciplinary excellence in the consortium. TEMPO will off er a proof of principle of tailored chronotherapeutics in mouse models for irinotecan, an active drug against colorectal cancers, and for seliciclib, currently in clinical testing. TEMPO will gather the corresponding human prerequisites and technology for subsequent application to patients. Three SMEs play a pivotal role for the impact of TEMPO on European health, economics and society. Novel and complementary in silico dynamic models of coordinated clock, cell cycle and pharmacology pathways will identify new therapeutic targets and delivery schedules of active molecules, thus improve drug development processes. New tools will enable personalized medicine to integrate the time dimension in routine implementation. TEMPO will reduce both therapeutic variability and attrition rates two major impediments for human health and pharmaceutical industries. However time can diff er between individuals as a result of genetic polymorphism and lifestyle diff erences. These determinants can then result in distinct optimal delivery patterns of cancer medication. TREATMENT Problem Non communicable chronic diseases represent the bulk of morbidity, disability and premature deaths in Europe and account for 75 % of the disability-adjusted life years. Among these, cancer represents the second cause of morbidity and mortality worldwide. Diff erences in the molecular characteristics of the tumor cells as well as diff erences in patient genetic origin, gender, age, lifestyle and circadian rhythms account for large variability in the time courses of cancer diseases and treatment response. TEMPO addresses the control of several key dynamic pathways in cancer drug metabolism and cellular proliferation by the circadian timing system. This biological system consists of a network of molecular clocks that times bodily and cellular functions along the 24 hours. Chronotherapeutics aim at the delivery of medications according to the 24-hour rhythms generated by the patient’s molecular clocks in order both to prevent adverse events and to improve overall therapeutic activity. Aim The general objective of TEMPO is to design mouse and in silico models refl ecting diff erent dynamic classes that predict for distinct optimal chronotherapeutic delivery patterns of anticancer drugs. Dynamic classes result from the identifi cation of the most discriminant parameters refl ecting cell cycle, pharmacology and physiology determinants that are controlled by the circadian clock thus impact on the temporal pattern in drug cytotoxicity. Optimal chronotherapeutic schedule can diff er in mice from diff erent strains or housed in diff erent environmental conditions as well as in cancer patients with diff erent gender and circadian timing status. TEMPO will provide a classifi cation based on functional genomics, proteomics and phenomics markers to be selected and validated along the development of the project. TEMPO will off er a proof of concept of tailored chronotherapeutics with a topoisomerase I inhibitor, and, a cyclin-dependent kinase inhibitor. The clinical relevance of the dynamic classes established in mice and in silico will be continuously reassessed along the development of the project, so as to also identify their counterpart in patients with corresponding specifi cation of optimal treatment delivery profi les. Primary emphasis will be put on the applications of TEMPO fi ndings to colorectal cancer. This disease aff ects 300 000 new persons in Europe each year and constitutes the second cause of deaths from cancer in both sexes. 217
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PROJECT SYNOPSES CANCER RESEARCH PR
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CANCER RESEARCH PROJECTS FUNDED UND
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TABLE OF CONTENTS FOREWORD - CANCER
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Prevention 97 EPIC 98 EUROCADET 100
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CANCER: COMBATING A COMPLEX DISEASE
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Biology Cancer is a disease ethat t
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p53 activators ASPP Partner 5 NFkap
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Keywords | Angiogenesis | vasculoge
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Keywords | Tumour-host interactions
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Keywords | Breast | metastasis | ge
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Keywords | Identifi cation of novel
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Keywords | Systems biology | modell
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Keywords | Oncology | anticancer th
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• public health research coupled
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Expected results We will construct
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Potential applications Our DNA is u
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Microscopic examination of tissue s
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Pluripotent embryonic stem cells ar
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• Decryption of the leukaemia cel
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• identifi cation of molecular ta
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A B C LT-HSC CSC The Cancer Stem Ce
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X-ray diff raction of target drug c
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using pathway-specifi c reporter ce
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Keywords | Kinases | pediatric panc
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Keywords | Lymphangiogenesis | angi
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Keywords | Breast cancer | metastas
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Keywords | Mitosis | phosphorylatio
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Keywords | Therapy | genome | telom
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Keywords | Multiple myeloma | cance
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Keywords | p53 tumour suppressor |
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Development of eff ective anti-canc
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Coordinator Patrick A. Curmi INSERM
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Drosophila as a model system for tu
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Normal cell growth and epithelial l
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effi ciently with cancer cell proli
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A high-throughput assay of transcri
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Coordinator Ewa Sikora Nencki Insti
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Expected results The SIROCCO consor
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Keywords | Epigenetics | gene regul
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Keywords | Hereditary | tricarboxyl
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Keywords | HSV-1 | hepatocellular c
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Keywords | Apoptosis | autophagy |
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Keywords | Tumour | host | signalli
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Aetiology The uncontrolled cell gro
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Coordinator Rosalind Eeles Reader i
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The parallelogram approach in CARCI
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Keywords | Melanoma | genetics | na
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Keywords | Virus | bacteria | HPV |
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Keywords | Breast | prostate | gene
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Prevention The fact that preventing
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Coordinator Elio Riboli Imperial Co
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Coordinator Jan Willem Coebergh Joh
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Coordinator Jose M a Benlloch Conse
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BAMOD Breath-Gas Analysis for Molec
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BioCare Molecular Imaging for Biolo
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These centres of excellence will in
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Expected results Optimise the benef
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114 Cell proliferation and apoptosi
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COBRED Colon and Breast cancer Diag
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DASIM Diagnostic Applications of Sy
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Expected results Primarily, the res
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Coordinator John A. Foekens Dept. o
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124 Aim Drop-Top has two major obje
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Coordinator Gorka Ochoa Progenika B
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Expected results The E.E.T.-Pipelin
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e developed by eTUMOUR is likely to
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Coordinator Angel Porgador Ben-Guri
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• the design of a compact assembl
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Potential applications We believe t
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Tumor initiation, progression to ma
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MolDiag-Paca Novel Molecular Diagno
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NEMO Nano based capsule-Endoscopy w
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OVCAD Ovarian Cancer - Diagnosis of
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P-MARK Validation of recently devel
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POC4life Multiparametric quantum do
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PROMET Prostate cancer molecular-or
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Micrometastasis in the bone marrow.
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and pharmaco-kinetics studies. This
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Coordinator Raffaella Giavazzi Isti
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• Development of tools for diagno
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Treatment Two major problems when t
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Coordinator Lluis M. Mir UMR 8121 C
Page 167 and 168: Potential applications ANGIOSTOP ha
Page 169 and 170: Green-fl uorescence protein- expres
Page 171 and 172: Coordinator Robert Hawkins Universi
Page 173 and 174: Expected results The BACULOGENES pr
Page 175 and 176: descriptors of the molecules to be
Page 177 and 178: Keywords | Therapeutic vaccine | im
Page 179 and 180: Keywords | Cancer chemotherapy | dr
Page 181 and 182: Keywords | Children | cancer | leuk
Page 183 and 184: Chimaeric TCR shown in context of n
Page 185 and 186: Andrea Splendiani Leaf Bioscience s
Page 187 and 188: Coordinator Anne O’Garra The Medi
Page 189 and 190: Coordinator Jacques Bartholeyns IDM
Page 191 and 192: Structure Driven Drug Design The in
Page 193 and 194: • acquire fundamental knowledge a
Page 195 and 196: Terry Jones Victoria University of
Page 197 and 198: Potential applications The use of t
Page 199 and 200: groups and management structures. T
Page 201 and 202: T. Barbui Azienda Ospedaliera-Osped
Page 203 and 204: Keywords | Mantle cell lymphoma | t
Page 205 and 206: Keywords | Hypoxia | HIF | pericell
Page 207 and 208: Keywords | Radiation-induced compli
Page 209 and 210: Keywords | Gene therapy | adenoviru
Page 211 and 212: Keywords | Dependence receptors | a
Page 213 and 214: Keywords | Photodynamic therapy | a
Page 215 and 216: Keywords | Ovarian cancer | thymidy
Page 217: Keywords | Quality assurance | clin
Page 221 and 222: Keywords | Anticancer therapy | onc
Page 223 and 224: Coordinator Monika Lusky Transgene
Page 225 and 226: 6 000 women over a three-year perio
Page 227 and 228: Keywords | Solid tumours | apoptosi
Page 229 and 230: Keywords | Lymphoma | leukaemia | v
Page 231: Coordinator Riccardo Dolcetti Centr
Page 234 and 235: CCPRB Cancer Control using Populati
Page 236 and 237: EPCRC The European Palliative Care
Page 238 and 239: EUROCAN+PLUS Feasibility Study for
Page 240 and 241: EUSTIR A European strategy for the
Page 242 and 243: NORMOLIFE Development of new therap
Page 245 and 246: Scientifi c Model Systems The compl
Page 247 and 248: Performance of benchmarking exercis
Page 249 and 250: • markers correlating with the im
Page 251 and 252: Indices - Keywords Indices - Partne
Page 253 and 254: ● disease markers 131 ● DNA dam
Page 255 and 256: ● renal 77 ● replication 219
Page 257 and 258: Bos, Nico A. 56 Boskovic, Darinka 2
Page 259 and 260: Geley, Stephan 159 Georgopoulos, Li
Page 261 and 262: Lingner, Joachim 54 Linial, Michal
Page 263 and 264: Ragno, Pia 115 Rainford, Martyn 92
Page 265 and 266: Vernos, Isabelle 22 Veronesi, Umber
Page 267 and 268: ● Centre Hospitalier Universitair
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● IFOM - Fondazione Istituto FIRC
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● National University of Ireland
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● University of Bari 174 ● Univ
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HOW TO OBTAIN EU PUBLICATIONS Our p
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