Cancer Research - Europa

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Apotherapy CD40 ligand-based modalities for the treatment of cancer Summary Keywords | Cancer | gene therapy | signalling | apoptosis | CD40 | phosphoinositide 3-kinase | metastasis | Cancer is a major disease according to the WHO Mortality Data base (2004) and is responsible for approximately 25 % of all deaths in the European Union. Epithelial tumours, such as those of the ovary, lung and oesophagus, have particularly poor prognosis, with only a minority of patients achieving a fi ve-year survival. Conventional treatments, including chemotherapy and radiotherapy, have limited effi cacy and frequently cause severe side-eff ects in patients. The Apotherapy project brings together expertise from academic and biotechnology sectors across seven European countries with the aim of developing and validating novel anti-cancer agents with a wide therapeutic index and minimal side-eff ects. The focal point of our research is the utilisation of combined approaches which attack the tumour cell at multiple levels, achieving maximal apoptosis while limiting the risk of drug resistance. These approaches involve the effi cient delivery of a pro-apoptotic molecule to cancer cells in combination with inhibitors of anti-apoptotic signal transduction pathways. Specifi cally, the project will formulate therapeutic strategies which exploit the ability of CD40 ligand (CD40L), a TNF family member, to reduce proliferation, promote apoptosis and activate anti-tumour immune responses selectively in cancer cells. Apotherapy will develop state-of-the-art vehicles for the effi cient delivery of CD40L to cancer cells, such as CD40L-encapsulated liposome formulations and recombinant adenoviruses expressing CD40L, and examine their in vitro and in vivo eff ects on tumour cell growth and metastasis. Apoptosis induced by CD40 engagement is dramatically augmented in the presence of inhibitors of the phosphoinositide 3-kinase (PI3 kinase) pathway, which is frequently found activated in human tumours. The Apotherapy project will expand on the development of novel PI3 kinase antagonists and evaluate their in vitro and in vivo capacity to kill tumour cells and to amplify the CD40L-mediated eff ects on carcinoma cell growth, angiogenesis and metastasis. Problem Cancer has a major health, social and fi nancial impact on Europe and its people. Current treatments include primary tumour resection and/or aggressive chemotherapy and radiotherapy in order to achieve both local control and eff ective therapy for distant metastases. Despite improved therapeutic regimens, mortality rates are still high. Moreover, the frequency of cancer incidence is predicted to increase and, as a result, its social and economic toll may reach even higher levels in the next decades. The growing cancer burden in Europe underscores the need to develop more effi cient antitumour agents with a view to increasing survival and improving the quality of life of cancer suff erers. Aim Apotherapy aims to combat cancer through an innovative combination strategy which targets cancer cells at multiple levels. One arm of this strategy is to encourage carcinoma cell apoptosis and immune recognition through the optimal activation of the CD40 pathway and the other is to suppress tumour cell survival mediated by the PI3 kinase signaling pathway. This strategy has been designed to achieve maximal inhibition of tumour growth while limiting the risk of side-eff ects. Expected results • The Apotherapy project will provide new information about targeting the CD40 and PI3 kinase pathways in solid tumours. • The project will develop and evaluate viral and non-viral vectors for the effi cient and tumour-specifi c delivery of anti-cancer agents in vivo. • Apotherapy will characterise novel antagonists and inhibitors of the anti-apoptotic PI3 kinase signalling pathway. • An extensive pre-clinical evaluation of CD40L delivery systems in combination with PI3 kinase pathway antagonists will be performed, aided by in vivo imaging technology. Potential applications The Apotherapy project will lead to the development of novel anti-cancer strategies which will be directly applicable to the clinic for the benefi t of cancer suff erers. The strong focus on translational research will translate R&D results into tangible benefi ts for health, science and economy in Europe. 166 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Green-fl uorescence protein- expressing lung tumours in mice are visualised by in vivo imaging. This technology is used to monitor tumour growth following treatment with recombinant adenoviruses. Coordinator Aristides Eliopoulos University of Crete Medical School Heraklion,Greece eliopag@med.uoc.gr Partners Marco Falasca University College London London, United Kingdom Massimo Broggini Istituto Mario Negri Milano, Italy TREATMENT Akseli Hemminki University of Helsinki Helsinki, Finland Jiri Ehrmann Univerzita Palackeho v Olomouci Olomouc, Czech Republic Angelica Loskog Uppsala University Uppsala, Sweden Steffen Panzner Novosom AG Halle, Germany Project number LSHC-CT 2006-037344 EC contribution € 1 895 900 Duration 36 months Starting date 01/10/2006 Instrument STREP Project website apotherapy.med.uoc.gr 167
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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
Page 118 and 119: COBRED Colon and Breast cancer Diag
Page 120 and 121: DASIM Diagnostic Applications of Sy
Page 122 and 123: Expected results Primarily, the res
Page 124 and 125: Coordinator John A. Foekens Dept. o
Page 126 and 127: 124 Aim Drop-Top has two major obje
Page 128 and 129: Coordinator Gorka Ochoa Progenika B
Page 130 and 131: Expected results The E.E.T.-Pipelin
Page 132 and 133: e developed by eTUMOUR is likely to
Page 134 and 135: Coordinator Angel Porgador Ben-Guri
Page 136 and 137: • the design of a compact assembl
Page 138 and 139: Potential applications We believe t
Page 140 and 141: Tumor initiation, progression to ma
Page 142 and 143: MolDiag-Paca Novel Molecular Diagno
Page 144 and 145: NEMO Nano based capsule-Endoscopy w
Page 146 and 147: OVCAD Ovarian Cancer - Diagnosis of
Page 148 and 149: P-MARK Validation of recently devel
Page 150 and 151: POC4life Multiparametric quantum do
Page 152 and 153: PROMET Prostate cancer molecular-or
Page 154 and 155: Micrometastasis in the bone marrow.
Page 156 and 157: and pharmaco-kinetics studies. This
Page 158 and 159: Coordinator Raffaella Giavazzi Isti
Page 160 and 161: • Development of tools for diagno
Page 163 and 164: Treatment Two major problems when t
Page 165 and 166: Coordinator Lluis M. Mir UMR 8121 C
Page 167: Potential applications ANGIOSTOP ha
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
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Keywords | Circadian | clocks | cel
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Keywords | Anticancer therapy | onc
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Coordinator Monika Lusky Transgene
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6 000 women over a three-year perio
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Keywords | Solid tumours | apoptosi
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Keywords | Lymphoma | leukaemia | v
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Coordinator Riccardo Dolcetti Centr
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CCPRB Cancer Control using Populati
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EPCRC The European Palliative Care
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EUROCAN+PLUS Feasibility Study for
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EUSTIR A European strategy for the
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NORMOLIFE Development of new therap
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Scientifi c Model Systems The compl
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Performance of benchmarking exercis
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• markers correlating with the im
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Indices - Keywords Indices - Partne
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● disease markers 131 ● DNA dam
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● renal 77 ● replication 219
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Bos, Nico A. 56 Boskovic, Darinka 2
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Geley, Stephan 159 Georgopoulos, Li
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Lingner, Joachim 54 Linial, Michal
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Ragno, Pia 115 Rainford, Martyn 92
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Vernos, Isabelle 22 Veronesi, Umber
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● 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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