Cancer Research - Europa

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Aim The THERADPOX project aims at engineering novel and optimised oncolytic pox- and adenoviruses for cancer therapy, specifi cally targeting colorectal, pancreatic and ovarian cancers. The innovative strategy of THERADPOX relies on the original engineering of OVs to render them safe, specifi c and effi cient for infection (binding and replication) and for the destruction of cancer cells through a combination of virotherapy with non-toxic chemotherapy in vivo. To achieve an enhancement of tumour cell infectivity of THERADPOX vectors, tumour-specifi c ligands, for which particular membrane proteins of cancer cells show high affi nity, will be incorporated in viral surface proteins and will be optimised. In addition, by modifying or exchanging ligand expression of THERADPOX OVs, one can imagine targeting other tumour types. The viral genome will also be engineered to ensure that viruses selectively replicate and express therapeutic proteins in tumour cells and that they spread widely through the tumour mass. Furthermore, capsid modifi ed oncolytic Ad vectors will be explored to overcome pre-existing immunity and delay an induced immune response. The oncolytic vectors (OVs) will be derived from the viral platforms described below: • vaccinia virus (VV): the advantages of VV as OV are a quick and effi cient life cycle, strong lytic activity and rapid cell-to-cell spreading. The virus can infect a wide variety of human tissues but does not cause any known human disease. VV was the fi rst widely used vaccine which resulted in the eradication of smallpox. As a result, the responses, safety profi le and adverse reactions have been extensively studied and documented; • myxoma virus (MV): MV causes myxomatosis in European rabbits but is non-pathogenic in man. However, myxoma virus productively infects a variety of human tumour cells (Sypula et al., 2004), suggesting a signifi cant potential for exploiting MV as a novel OV platform; • adenovirus (Ad): one of the most extensively studied viruses which have been engineered for gene therapy and for virotherapy of cancer, particularly serotypes 2 (Ad2) and 5 (Ad5). The virus is endemic in the human population and its natural pathogenicity is associated with mild respiratory infections (common cold). It can be grown easily and to high titres, and the methodology to generate recombinant viruses is well established. Expected results THERADPOX OVs will be engineered to: • selectively target cancer cells in vivo (up to a 100-fold increase of tumour cell infection can be expected: 100 cancer cells infected for 1 normal cell infected) (M30); • selectively replicate and propagate in tumour cells in vivo (expectations are a 100-fold increase of viral yield in tumour cells versus normal cells) (M32); • widely spread within tumours in vivo (a statistically significant increase of the therapeutic index is expected) (M30); • specifi cally render cancer cells sensitive to chemotherapy in vivo: OVs will be engineered to express in the infected cancer cells prodrug- converting enzymes, enabling the conversion of a non-toxic molecule (given orally or intravenously) to toxic compounds (a statistically signifi cant increase of the therapeutic index is expected) (M36); • overcome the pre-existing immunity and to delay the induced adenoviral immune response, concerning oncolytic Ad (M36). Potential applications The THERADPOX project contributes to supporting the Programme of Community action in the fi eld of public health (2003-2008) (1786/2002/EC) by: • promoting and improving health, with a view to reducing avoidable morbidity: THERADPOX will develop new OVs to cure patients aff ected with colorectal, pancreatic and ovarian cancers; • reacting rapidly to health threats: THERADPOX vectors are designed to eradicate tumours. Their selectivity for one tumour type relies on the tumour cell selectivity of specifi c ligands. Thus, by only changing the ligand in THERADPOX OVs, one can imagine targeting and effi - ciently and rapidly eradicating other tumour types that may be a threat to human health in the future; • promoting better knowledge and communication fl ows, thus allowing a greater involvement of individuals in decisions that concern their health. THERADPOX includes specifi c tasks for: • communicating about the knowledge, impacts and benefi ts of the project; • disseminating results and information, in a simple, clear and sound way about the work undertaken within THERADPOX to the scientifi c community as well as to the community population, with the ultimate goal to improve the quality of life. 220 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Coordinator Monika Lusky Transgene SA Strasbourg, France lusky@transgene.fr Partners Ramon Alemany Institut Català d’Oncologia L’Hospitalet de Llobregat Barcelona, Spain ralemany@ico.scs.es Stéphane Bertagnoli École nationale vétérinaire de Toulouse UMR1225 IHAP/ENVT (INRA) Toulouse, France bertagnoli@envt.fr Richard Iggo University Court of St. Andrews St. Andrews, United Kingdom richarad.iggo@isrec.ch Harry Jalonen Delsitech Ltd Turku, Finland harry.jalonen@delsitech.com TREATMENT Akseli Hemminki University of Helsinki Helsinki, Finland akseli.hemminki@helsinki.fi Mohammed Benbouchaib Newlab Nancy, France boussetta@newlab.fr Gerd Sutter Paul-Ehrlich Institute (PEI) Langen, Germany sutge@pei.de Victoria Smith Niko Bausch Oncotest GmbH Freiburg, Germany niko.bausch@oncotest.de David Koubi ACIES SAS Lyon, France david.koubi@acies.fr Project number LSHB-CT-2004-018700 EC contribution € 2 411 006 Duration 36 months Starting date 02/11/2005 Project website www.theradpox.org 221
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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
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 and 218: Keywords | Quality assurance | clin
Page 219 and 220: Keywords | Circadian | clocks | cel
Page 221: Keywords | Anticancer therapy | onc
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
Page 269 and 270: ● IFOM - Fondazione Istituto FIRC
Page 271 and 272: ● National University of Ireland
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● University of Bari 174 ● Univ
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