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EuroBoNeT European Network to Promote Research into Uncommon Cancers in Adults and Children: Pathology, Biology and Genetics of Bone Tumours Summary Primary bone tumours are rare, accounting for ~0.2 % of the cancer burden. Children and young adolescents are frequently aff ected. The aggressiveness of these tumours has a major impact on morbidity and mortality. Though progress has been made in pathological and genetic typing, the aetiology is largely unknown. Advances in therapeutic approaches have increased survival rates, but a signifi cant numbers of patients (~40 %) still die. Within the EuroBoNeT, staff exchange, share of material and technologies, as well as the organisation of training courses, will be used to increase and disseminate knowledge of primary bone tumours. Exchange of material, standard operating protocols, and the use of technology platforms will enable us to obtain statistically signifi cant datasets. A joint programme will contribute in obtaining molecular portraits of tumours, separated into four research lines: RL1: cartilaginous tumours; RL2: osteogenic tumours and related sarcomas; RL3: osteoclastogenesis and giant cell tumours of bone; and RL4: the Ewing family of tumours. The tumours will be examined by genome-wide expression, genomic aberration studies, and specifi c hypothesis-driven approaches (RNA/protein expression and mutation analysis). In vitro studies will be used to obtain knowledge of normal growth and diff erentiation, and this may help to identify markers for malignant transformation and/or progression, as well as identifi cation of therapeutic targets. Dissemination of knowledge will be achieved by training courses on bone and soft tissue pathology. This is essential since patients do not normally present themselves at centres, and it is important to share such knowledge. Problem Bone sarcomas are rare and represent a group of cancers that occur predominantly in children and young adults. Intrinsic to their aggressive behaviour, these tumours are lethal in about 40 % of patients despite modern multimodality therapy. Although substantial progress has been made over the last 10 years in understanding these tumours at the biological, pathologic and genetic level, this has not been translated into more eff ective therapies so far. 36 Keywords | Bone tumour | chondrosarcoma | osteosarcoma | giant cell tumour of bone | Ewing’s sarcoma | osteochondroma | Paget disease of bone | chondrogenesis | osteogenesis | The 2002 WHO classifi cation recognises 32 diff erent entities of bone tumours. Achieving signifi cant numbers to study the diff erent types of bone tumours, which are already rare as a group, is diffi cult. The research into these tumours is often performed in relatively small research groups, which are inherently hampered by the lack of availability of substantial numbers of cases, as well as lacking a critical technical and/or multidisciplinary mass. Interestingly, despite their rareness, these tumours provide excellent examples for unravelling oncogenic mechanisms. The main problems are: • collecting enough tumours to obtain reliable signifi cant statistical results, also when comparing subtypes based on locations, grade, etc.; • since osteogenic and Ewing’s family of tumours are considered orphan diseases, pharmaceutical companies will not invest in developing new drugs; • chemotherapeutic treatment can be toxic for the patient or not eff ective, and there are no tools that predict which patients are hypersensitive or which tumours are refractory; • cartilaginous tumours are resistant to treatment other than surgery. This can be mutilating and it is not always feasible to remove the whole tumour (for instance in the pelvic area); • a small percentage of benign cartilaginous tumours develop into malignant chondrosarcomas, but there are no clues to recognising the ones that will deteriorate; • the biological behaviour of giant cell tumours is variable and cannot be predicted so far. In a small proportion of tumours, synchronous or metachronous metastases develop; • the biology of normal chondrogenesis and osteogenesis is complex. A better under-standing of the pathways involved could provide clues to the biology of bone tumours. Aim The above-mentioned major problems will be handled by EuroBoNeT in the following ways: • to overcome the spread of samples and lack of critical technical and/or multidisciplinary mass in some of the institutes, the main objective will be to reach integration through sharing of samples, sharing of technologies and incorporating all information gathered by the diff erent partners. This will be done through staff exchange, core facilities, a virtual BioBank and combining each others’ experimental results; • the EuroBoNeT will characterise the tumours in the different research lines by proteomics, genome-wide expression analysis, and genomic array. This will provide a large data set, which can be compared within and between the diff erent tumour (sub)types. These data will be used for: • identifi cation of loci involved in conferring hypersensitivity or chemotherapy resistance; CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
• identifi cation of molecular targets for therapy; • identifi cation of markers involved in malignant transformation; • identifi cation of genes/pathways involved in disease progression. • by studying the molecular mechanisms involved in osteoclasto genesis and chondrogenesis (using in vitro models), EuroBoNeT aims to identify new mechanisms that could also play a role in bone tumourigenesis, and provide clues for the identifi cation of new diagnostic and/or prognostic markers. Expected results The establishment of a lasting network in which samples will be ex changed and results combined and discussed, and that will be able to: • provide uniform guidelines for bone tumour pathology; • play a role in the development of: • new diagnostic markers, • new prognostic markers, • markers to predict the eff ect of chemotherapeutics, • new drug treatment. Coordinator Pancras CW Hogendoorn Leiden University Medical Center Dept. of Pathology Leiden, The Netherlands eurobonet@lumc.nl Partners Piero Picci Istituto Ortopedico Rizzoli Bologna, Italy Sakari Knuutila University of Helsinki Helsinki, Finland Lars-Gunnar Kindblom Royal Orthopaedic Hospital NHS Trust Birmingham, United Kingdom Ramses Forsyth N Goormaghtigh Institute of Pathology Gent, Belgium Wim Wuyts University of Antwerp Antwerp, Belgium Antonio Llombart-Bosch University de Valencia Valencia, Spain Chris Poremba Heinrich-Heine-University Düsseldorf Düsseldorf, Germany Pierre Mainil University of Bern Bern, Switzerland Nick Athanasou University of Oxford Oxford, United Kingdom Enrique de Alava University de Salamanca-CSIC Centro de Investigacion del Cancer Salamanca, Spain Ola Myklebost University of Oslo Norwegian Radium Hospital Oslo, Norway Søren Daugaard Rigshospitalet Copenhagen, Denmark Fredrik Mertens University of Lund Lund, Sweden Thomas Aigner University of Leipzig Leipzig Germany Raf Sciot Catholic University of Leuven University Hospital Leuven, Belgium Horst Bürger Westfalische Wilhelmuniversity Münster Münster, Germany Angelo Paolo Dei Tos Hospital of Treviso Treviso, Italy Miklös Szendröi Semmelweis University Budapest Budapest, Hungary Wiltrud Richter Stiftung Orthopadische Universitatsklinik Heidelberg Heidelberg, Germany Project number LSHC-CT-2006-018814 EC contribution € 13 218 960 Duration 60 months Starting date 01/02/2006 Instrument NoE Project website www.eurobonet.eu Jos Joore Pepscan Systems BV Lelystad, The Netherlands Jan Schouten MRC-Holland Amsterdam, The Netherlands Zsolt Hollo Solvo Biotechnology, Inc. Budapest, Hungary Peter Riegman Erasmus Medical Center Rotterdam, The Netherlands Adrienne Flanagan University College of London London, United Kingdom BIOLOGY 37
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: • Decryption of the leukaemia cel
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 and 46: using pathway-specifi c reporter ce
Page 47 and 48: Keywords | Kinases | pediatric panc
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
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 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
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:
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