Cancer Research - Europa

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Pierre Hupperets University Hospital Maastricht, The Netherlands Jacek Jassem Medical University of Gdansk Gdansk, Poland Jose Manuel Leal da Silva Portuguese Institute of Oncology Porto Centre Porto, Portugal Mikhail Lichinister N. N. Blokhin Cancer Research Centre Moscow, Russian Federation Tanja Cufer Institute of Oncology Ljubljana, Slovenia Olivia Pagani Institute of Oncology of Southern Switzerland Mendrisio, Switzerland Gul Basaran Marmara University Medical School Hospital Istanbul, Turkey Michel Ballieu European CanCer Organisation (ECCO) Brussels, Belgium Susan Knox Mary Buchanan Europa Donna – The European Breast Cancer Coalition Milan, Italy Fernando Schmitt Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto, Portugal 224 Michael Atkinson German Research Center for Environmental Health Munich, Germany Laura van ’t Veer Agendia BV Amsterdam, The Netherlands Marc Buyse International Institute for Drug Development Brussels, Belgium Josep Baselga Fundacion Institut per la Recerca Vall d’Hebron Barcelona, Spain Jose Vasquez Grupo Español de Estudio, Tratamiento y otras Estrategias Expirementales en Tumores Sólidos (SOLTI) Madrid, Spain Mauro Delorenzi Swiss Institute of Bioinformatics Lausanne, Switzerland Adrian Harris The Chancellors Masters and Scholars of the University of Oxford Oxford, United Kingdom Alistair Thomson The University of Dundee Dundee, United Kingdom Project number LSHC-CT-2004-503426 EC contribution € 7 000 000 Duration 84 months Starting date 01/03/2004 Instrument NoE Project website www.breastinternational group.org CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Keywords | Solid tumours | apoptosis | tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) | receptor-selective TRAIL mutants | TNF ligand-mimicking peptides | intracellular peptide inhibitors | computational rational protein design | directed evolution | tailor-made therapy | primary tumour culture | cell-based delivery systems of anti-cancer genes | GLP/GMP procedures | TRIDENT Therapeutic molecules for treatment of solid tumours by modulating death receptor-mediated apoptosis Summary The effi cacy of current treatments for some types of solid tumours is disappointingly poor. New therapies using novel tumour-selective anti-cancer agents are necessary. A major aim of anti-tumour therapies is to inhibit proliferation and induce death of tumour cells without aff ecting normal cells. In this regard, members of TNF ligand/receptor family are of interest since they regulate both apoptosis (programmed cell death) and cell proliferation. One TNF family member, TRAIL, is of particular interest since it selectively induces death of tumour cells without aff ecting normal cells. Currently, TRAIL and TRAIL-specifi c antibodies are being investigated as anti-cancer agents. However, a major drawback to TRAIL’s effi cacy is that it binds to multiple receptors, not all of which transduce an apoptotic signal. Previously, we developed receptor-selective TRAIL variants which are potent inducers of apoptosis in various tumour cells, are more effi cacious than native TRAIL, and display synergistic eff ect in combination with other chemotherapy treatments or radiotherapy. This proposal will investigate and characterise TRAIL variants pre-clinically in solid tumour models and defi ne new treatment protocols in combination with already proven treatments. Furthermore, we will elucidate the role of other TNF receptor family members in signalling in tumour cell survival/death. Biochemical and structural characterisation will identify new targets for molecular cancer therapy while computational design and molecular evolution techniques will be used to develop novel receptor-selective apoptosisinducing agonists. We will also develop intracellular acting agents (intracellular-acting peptides inhibiting pro-survival signals; intracellular peptide inhibitors), which will block the unwanted proliferative/anti-apoptotic signals activated by some TNF members. The tumoricidal activity of these lead molecules will be tested using conventional, viral and cell based delivery strategies which will utilise peptide sequences to specifi cally target them to tumour cells. TREATMENT Problem With almost 3 million new cases each year and 1.7 million deaths, cancer is an important public health problem in Europe. The ageing of the European population will cause these numbers to continue to increase. The most common cancers are lung, colorectal and breast cancers. The available treatments for these solid cancers and the outcome of the treatments are not satisfactory. New therapeutic strategies and novel tumourselective anti-cancer agents are necessary in order to improve the treatment of these and other solid tumours. Aim The ultimate aim of the TRIDENT project is to develop novel molecules that target critical apoptotic signalling pathways important in the formation of various solid tumours. The specifi c objectives are: • to develop of novel apoptosis-inducing agonists and proliferation antagonists using state-of-the art, computer based rational design and directed evolution techniques; • to gain in-depth knowledge on the role of the TNF ligand-receptor family interactions in the carcinogenesis of solid tumours, both at a molecular and structural level; The objective of TRIDENT is to channel death receptor activation towards tumour cell apoptosis. Activation of cell surface death receptors do not only induce apoptosis of the receptor carrying cell but can simultaneously activate compensatory, pro-survival pathways, which limits the use of this pathway to kill cancerous cells. The TRIDENT project aims to generate TNF ligand variants that only bind to the death-inducing members of the TNF receptor family, not to decoy TNF receptors (selective ligand) and design cell permeable peptide inhibitors (intracellular inhibitors; IC inh) against anti-apoptotic molecules. These novel molecules used in combination can maximize tumour cell killing. 225
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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
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Potential applications ANGIOSTOP ha
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Green-fl uorescence protein- expres
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Coordinator Robert Hawkins Universi
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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 and 218: Keywords | Quality assurance | clin
Page 219 and 220: Keywords | Circadian | clocks | cel
Page 221 and 222: Keywords | Anticancer therapy | onc
Page 223 and 224: Coordinator Monika Lusky Transgene
Page 225: 6 000 women over a three-year perio
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
Page 269 and 270: ● IFOM - Fondazione Istituto FIRC
Page 271 and 272: ● National University of Ireland
Page 273 and 274: ● University of Bari 174 ● Univ
Page 275 and 276: HOW TO OBTAIN EU PUBLICATIONS Our p
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