Cancer Research - Europa

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Coordinator Kristian Helin Biotech Research and Innovation Centre Copenhagen, Denmark kristian.helin@bric.dk Partners Pier Giuseppe Pelicci Istituto Europeo di Oncologia Milan, Italy piergiuseppe.pelicci@ifom-ieo-campus.it Anton Berns René Bernards Maarten van Lohuizen Nederlands Kankerinstituut Antoni van Leeuwenhoek Ziekenhuis Amsterdam, The Netherlands a.berns@nki.nl r.bernards@nki.nl m.v.lohuizen@nki.nl Maria Blasco Manuel Serrano Centro Nacional de Investigaciones Oncológicas Madrid, Spain mblasco@cnio.es mserrano@cnio.es 44 Manuela Baccarini Institute of Microbiology and Genetics University of Vienna Vienna, Austria manuela.baccarini@univie.ac.at Clemens Schmitt Max-Delbrück-Centre for Molecular Medicine Charité, Campus-Virchow-Klinikum Hematology-Oncology Berlin, Germany clemens.schmitt@charite.de Martin Eilers Philipps-Universität Marburg Institute for Molecular Biology and Tumour Research Marburg, Germany eilers@imt.uni-marburg.de Andreas Trumpp Michel Aguet ISREC Epalinges, Switzerland andreas.trumpp@isrec.unil.ch michel.aguet@isrec.unil.ch Karen Vousden Beatson Institute for Cancer Research Glasgow, United Kingdom k.vousden@beatson.gla.ac.uk Anne Dejean Institut Pasteur Paris, France adejean@pasteur.fr Bernhard Sixt Agendia BV. Amsterdam, The Netherlands bernhard.sixt@agendia.com György Kéri Vichem Chemie Research Ltd Budapest, Hungary Keri@vichem.hu Project number LSHC-CT-2003-506803 EC contribution € 8 200 000 Duration 48 months Starting date 01/01/2004 Instrument IP Project website www.imt.uni-marburg. de/intact CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Keywords | Kinases | pediatric pancers | new drugs | KidsCancerKinome Selecting and validating drug targets from the Human kinome for high risk paediatric cancers Summary Selecting and validating drug targets from the human kinome for high risk pediatric cancers. KidsCancerKinome will make a comprehensive analysis of the human protein kinase family. Protein kinases are already excellent targets for many small inhibitory molecules and antibodies designed for adult tumors. Six aggressive childhood tumors (neuroblastoma, medulloblastoma, rhabdomyosarcoma, osteosarcoma, Ewing tumor, acute lymphocytic leukemia) will be addressed, which are responsible for 50 % of childhood cancer deaths. Viral shRNA libraries will be applied to test the entire human kinase gene family for tumor-driving kinases in cell lines. They will subsequently be analyzed for mutations and functional parameters in large cohorts of tumor samples. siRNA mediated inactivation in larger cell line panels will critically validate suitable kinases as drug targets. Novel kinase inhibitors being developed for adult oncology will be tested for in vitro activity against the tumor-driving kinases. When no inhibitor is available, a novel generation of siRNA based nucleic acid drugs (LNAs) will be applied. Successful compounds will be taken further to in vivo validation in established xenograft models of the six childhood tumor types. Problem Each year 15 000 European children are diagnosed with cancer and 25 % die of this disease. Survivors frequently suff er from late side-eff ects of current treatments regimes. Translational research of childhood tumors to identify molecular targets for novel generations drugs is therefore urgently needed. In addition, novel targeted drugs currently developed for adult tumors have to become available for children. Indeed, the EU launched in 2007 a paediatric Medicines Regulation to stimulate drug evaluation in children. Nine European research centers devoted to molecularbiologic and pharmacologic studies of childhood cancers and two SMEs therefore engaged in the KidsCancerKinome project. BIOLOGY Aim The overall aim of the KidsCancerKinome project is to systematically explore the human kinase family for targeted therapy development for children with cancer can be broken down in the following objectives. • In silico analysis of the ITCC microarray database (in which we established the expression profi les of 600 childhood tumours), for expression profi les of all protein kinase family members. The expression patterns will be used to prioritize the analyses of the protein kinases. • Functional high-throughput screening of the full >500 member kinase gene family for essential protein kinases in 24 childhood cancer cell lines, using a kinase-specifi c viral siRNA library and bar-coding-based read out system. • Screening of extended cell line panels of the six selected tumour types for dependency on known cancer-related protein kinases and the protein kinases identifi ed in step 2, by single-kinase siRNA. • Mutation analysis of ‘tumour-driving’ protein kinases (identifi ed in steps 1-3) in series of paediatric tumour samples. • Analysis of large clinical series of tumour samples for presence and activation status of protein kinases identifi ed in step 1-3 by immunohistochemistry. • In vitro testing of available small molecules for inhibition of the protein kinases identifi ed in step 1-3. • In vitro testing of LNA kinase inhibitors for protein kinases identifi ed in step 1-3 for which no small molecule drugs are available. • Validation of selected small molecule and LNA kinase inhibitors in nude mouse transplants of childhood tumours. • Pharmacokinetic and pharmacodynamic studies of LNA’s for protein kinases selected in step 1-7 to identify LNA antagonist kinase inhibitor for the drug development pipeline of Santaris. Expected results KidsCancerKinome will contribute to a better understanding of the unique pediatric tumor biology and to the development of new drugs. Potential applications Identifi cation of new drugable targets and development of new specifi c treatments for childhood malignancies. 45
Page 1 and 2: PROJECT SYNOPSES CANCER RESEARCH PR
Page 3 and 4: CANCER RESEARCH PROJECTS FUNDED UND
Page 5 and 6: TABLE OF CONTENTS FOREWORD - CANCER
Page 7 and 8: Prevention 97 EPIC 98 EUROCADET 100
Page 9 and 10: CANCER: COMBATING A COMPLEX DISEASE
Page 11 and 12: Biology Cancer is a disease ethat t
Page 13 and 14: p53 activators ASPP Partner 5 NFkap
Page 15 and 16: Keywords | Angiogenesis | vasculoge
Page 17 and 18: Keywords | Tumour-host interactions
Page 19 and 20: Keywords | Breast | metastasis | ge
Page 21 and 22: Keywords | Identifi cation of novel
Page 23 and 24: Keywords | Systems biology | modell
Page 25 and 26: Keywords | Oncology | anticancer th
Page 27 and 28: • public health research coupled
Page 29 and 30: Expected results We will construct
Page 31 and 32: Potential applications Our DNA is u
Page 33 and 34: Microscopic examination of tissue s
Page 35 and 36: Pluripotent embryonic stem cells ar
Page 37 and 38: • Decryption of the leukaemia cel
Page 39 and 40: • identifi cation of molecular ta
Page 41 and 42: A B C LT-HSC CSC The Cancer Stem Ce
Page 43 and 44: X-ray diff raction of target drug c
Page 45: using pathway-specifi c reporter ce
Page 49 and 50: Keywords | Lymphangiogenesis | angi
Page 51 and 52: Keywords | Breast cancer | metastas
Page 53 and 54: Keywords | Mitosis | phosphorylatio
Page 55 and 56: Keywords | Therapy | genome | telom
Page 57 and 58: Keywords | Multiple myeloma | cance
Page 59 and 60: Keywords | p53 tumour suppressor |
Page 61 and 62: Development of eff ective anti-canc
Page 63 and 64: Coordinator Patrick A. Curmi INSERM
Page 65 and 66: Drosophila as a model system for tu
Page 67 and 68: Normal cell growth and epithelial l
Page 69 and 70: effi ciently with cancer cell proli
Page 71 and 72: A high-throughput assay of transcri
Page 73 and 74: Coordinator Ewa Sikora Nencki Insti
Page 75 and 76: Expected results The SIROCCO consor
Page 77 and 78: Keywords | Epigenetics | gene regul
Page 79 and 80: Keywords | Hereditary | tricarboxyl
Page 81 and 82: Keywords | HSV-1 | hepatocellular c
Page 83 and 84: Keywords | Apoptosis | autophagy |
Page 85 and 86: Keywords | Tumour | host | signalli
Page 87 and 88: Aetiology The uncontrolled cell gro
Page 89 and 90: Coordinator Rosalind Eeles Reader i
Page 91 and 92: The parallelogram approach in CARCI
Page 93 and 94: Keywords | Melanoma | genetics | na
Page 95 and 96: Keywords | Virus | bacteria | HPV |
Page 97 and 98:
Keywords | Breast | prostate | gene
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Prevention The fact that preventing
Page 101 and 102:
Coordinator Elio Riboli Imperial Co
Page 103 and 104:
Coordinator Jan Willem Coebergh Joh
Page 105:
Coordinator Jose M a Benlloch Conse
Page 108 and 109:
BAMOD Breath-Gas Analysis for Molec
Page 110 and 111:
BioCare Molecular Imaging for Biolo
Page 112 and 113:
These centres of excellence will in
Page 114 and 115:
Expected results Optimise the benef
Page 116 and 117:
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
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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
Page 148 and 149:
P-MARK Validation of recently devel
Page 150 and 151:
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
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 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 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
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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:
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