Cancer Research - Europa

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Cancer immunotherapy with defi ned tumor antigens: antigens that have been identifi ed as specifi cally expressed by the tumor cells are used in therapeutic vaccination trials to stimulate anti-tumor lymphocytes. Patients are monitored for signs of tumor regression and for the induction of anti-tumor immune responses. 176 Coordinator Thierry Boon de Duve Institute Brussels, Belgium thierry.boon@bru.licr.org Partners Hans-Georg Rammensee Eberhard-Karls-Universität Tübingen Tübingen, Germany Sebastian Amigorena Ludger Johanness Institut Curie Paris, France Marc Bonneville Anne-Marie Schmitt-Verhulst Institut Nationale de la Santé et de la Recherche Médicale Paris, France Pedro Romero Ludwig Institute for Cancer Research Epalinges, Switzerland Vincenzo Cerundolo University of Oxford Oxford, United Kingdom Alexander Eggermont Erasmus MC Rotterdam Rotterdam, The Netherlands Carl Figdor Stichting Katholieke Universiteit Nijmegen, The Netherlands Federico Garrido Fundacion Virgen de las Nieves Granada, Spain Günter Hämmerling Dirk Schadendorf Bruno Kyewski Deutsches Krebsforschungszentrum Heidelberg, Germany Ulrich Keilholz Charité Universitatsmedizin Berlin Berlin, Germany Cornelis Melief Leiden University Medical Center Leiden, The Netherlands Chiara Castelli Fondazione Istituto Natzionale Tumori Milan, Italy Gerold Schuler Friedrich Alexander Universität Erlangen-Nürnberg Erlangen, Germany Thomas Wölfel Ugur Sahin Hansjoerg Schild Johannes Gutenberg-Universität Mainz Mainz, Germany Eric Tartour Université René Descartes Paris, France Muriel Moser Université Libre de Bruxelles Brussels, Belgium Project number LSHC-CT-2006-518234 EC contribution € 12 185 102 Duration 48 months Starting date 01/03/2006 Instrument IP Project website www.cancerimmuno therapy.eu Kris Thielemans Vrije Universiteit Brussel Brussels, Belgium Hélène Sicard Innate Pharma SA Marseille, France Brigitte Dreno Centre Hospitalier Universitaire de Nantes Nantes, France Jochen Probst CureVac the RNA people Tübingen, Germany Vincenzo Russo Fondazione San Raffaele del Monte Tabor Milan, Italy CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Keywords | Cancer chemotherapy | drug resistance | toxicity | lung cancer | melanoma | CHEMORES Molecular mechanisms underlying chemotherapy resistance, therapeutic escape, effi cacy and toxicity Summary The CHEMORES project aims to improve the outcome of cancer chemotherapy by developing novel tools to predict tumour response to treatment as well as individual toxicity to chemotherapy. The project will thus seek to identify and validate mechanisms of intrinsic and acquired chemotherapy resistance, as well as predictors of effi cacy and of individual toxicity. This is achieved by integrating the work of groups conducting large clinical trials with preclinical research groups, as well as with state-of-the-art platforms for genomic and proteomic analyses and bioinformatics. The participants have chosen to focus on melanoma and lung cancer as model tumours of separate histogenetic types exhibiting intrinsic resistance and/or a high degree of acquired resistance to chemotherapy. Candidate mechanisms of drug resistance and therapeutic effi cacy will be identifi ed using genomic and proteomic analyses of sequential tumour samples and paired sera obtained before and after chemotherapy, as well as experimental systems, including in vitro studies of tumuor cell lines, transplanted human tumours and novel animal tumour models. These putative mechanisms will then be validated in further analyses of larger sets of tumour biopsies from patients. Functional studies of novel mechanisms and pathways will be also performed using in vitro systems and animal models. The result of these activities will thus be a set of clinically and functionally validated mechanisms of chemotherapy resistance and therapeutic effi cacy. Likewise, large-scale genomic analyses of patients receiving chemotherapy as part of clinical trials will be performed, in order to validate novel markers of individual toxicity following chemotherapy. Problem Resistance to systemic chemotherapy still remains one of the greatest problems in clinical oncology, and contributes to the death of a large number of cancer patients. Despite extensive eff orts, no signifi cant prog ress has been made in solving this fundamental problem during the last decades. Not only have effi cient means to overcome chemotherapy TREATMENT resistance not been identifi ed, but also the development of clinically useful tools to predict response to chemotherapy has been largely unsuccessful. The diff erent aspects of the chemoresistance problem are well illustrated in the two model tumours that will be studied. The two main subtypes of lung cancer are small cell lung cancer (SCLC) which is highly chemosensitive with response rates of 80 % to chemotherapy; and non-small cell lung cancer (NSCLC) that is moderately chemosensitive with response rates of 30-60 %. For all stages and types of lung cancer (NSCLC/SCLC), relapse after primary therapy is common, at which stage most patients have developed an acquired resistance to chemotherapy and seldom respond to second line treatment. In lung cancer, a therapeutic plateau has thus been reached with existing cytotoxic drugs and further improvements in survival are dependent on our understanding of the molecular mechanisms of chemoresistance. There is no eff ective systemic therapy for metastatic melanoma and only a small minority of patients with melanoma respond to chemotherapy, which also has no discernible impact upon median overall survival. In the adjuvant setting interferon-alfa (IFN) is the only agent that has demonstrated a consistent eff ect on relapse-free survival, but without a signifi cant impact on overall survival. We have as yet no tools to identify the patient population that benefi ts from treatment with IFN. Thus, improved knowledge regarding mechanisms of resistance is needed in order both to develop predictive tests and to modulate resistance and thus improve the therapeutic outcome in melanoma. Cancer chemotherapy is frequently associated with severe toxic side-eff ects. Novel tools to identify individuals with an increased risk of developing severe side-eff ects are required in order to avoid such adverse events. Aim The overall aim of CHEMORES is to improve the outcome of cancer chemotherapy by developing novel tools to predict tumour response to treatment as well as individual toxicity to chemotherapy. Expected results The novel knowledge obtained through the project will lead to new tools for prediction of treatment outcome as well as toxicity of chemotherapy. This knowledge may also be used to identify and prepare for pre-clinical development of potential novel modulators of drug resistance based on validated mechanisms and pathways. The new information obtained in CHEMORES will be disseminated to the medical profession and other key stakeholders, such as health care providers, patient organisations and policy-makers. 177
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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
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 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: Keywords | Therapeutic vaccine | im
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 and 226: 6 000 women over a three-year perio
Page 227 and 228: 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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HOW TO OBTAIN EU PUBLICATIONS Our p
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