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14 Potential applications The project will lead to the identifi cation of a number of potential targets towards the tumour vasculature. Within the ANGIOTARGETING consortium there are a number of activities aiming at developing novel therapeutic strategies towards identifi ed and validated targets. Some of these strategies will be applied and assessed in preclinical and clinical trials. Coordinator Rolf Bjerkvig University of Bergen Bergen, Norway rolf.bjerkvig@biomed.uib.no Partners Helge Wiig, Karl-Henning Kalland and Inge Jonassen University of Bergen Bergen, Norway helge.wiig@biomed.uib.no kalland@gades.uib.no inge.jonassen@ii.uib.no Francesco Bertolini European Institute of Oncology Milan, Italy francesco.bertolini@ieo.it Lena Claesson-Welsh University of Uppsala Uppsala, Sweden lena.welsh@genpat.uu.se Peter ten Dijke Leiden Medical University Center Leiden, The Netherlands p.ten_dijke@lumc.nl Michael Kubbutat Proqinase/KTB Tumorforschungs GmbH Freiburg, Germany m.kubbutat@proqinase.com Arjan W. Griffioen and Johannes Waltenberger University Hospital Maastricht Maastricht, The Netherlands aw.griffioen@path.unimaas.nl waltenberger@cardio.azm.nl Adrian Harris University of Oxford United Kingdom aharris.lab@cancer.org.uk Henk Broxterman Vrije Universiteit Medical Center Amsterdam Amsterdam, The Netherlands h.broxterman@vumc.nl Taina Pihlajaniemi University of Oulu Oulu, Finland taina.pihlajaniemi@oulu.fi Eva Sykova Institute of Experimental Medicine Prague, Czech Republic sykova@biomed.cas.cz Simone Niclou Centre de la recherche public de la santé Luxembourg simone.niclou@crp-sante.healthnet.lu Karl Tryggvason and Yihai Cao The Karolinska Institute Stockholm, Sweden karl.tryggvason@mbb.ki.se yihai.cao@mtc.ki.se Peter Vajkozcy Charité-Universitatsmedizin Berlin, Germany peter.vajkoczy@charite.de Leo Hofstra PharmaTarget BV Maastricht, The Netherlands l.hofstra@cardio.azm.nl Project number LSHC-CT-2004-504743 EC contribution € 6 000 000 Duration 54 months Starting date 01/11/2004 Instrument IP Project website www.uib.no/med/ angiotargeting/ CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Keywords | Tumour-host interactions | tumour targeting | Anti-tumour targeting Modulation of the Recruitment of the Vessels and Immune Cells by Malignant Tumours: Targeting of Tumour Vessels and Triggering of Anti-Tumour Defence Mechanisms Summary All malignant tumours acquire the capacity for efficient recruitment of blood vessels, which are absolutely necessary for tumour growth beyond a certain size. They also frequently stimulate lymphangiogenesis supporting dissemination of tumour cells, not only via the blood vasculature but also via the lymphatic system, leading to metastasis. Vessel growth is promoted by sprouting angiogenesis and the homing of bone marrow progenitor cells into the tumours and tumour vessels. The extensive vascularisation facilitates the invasion of cells of the innate and adaptive immune system, which stay largely functionally suppressed by the tumour environment, and even contribute to angiogenesis and tumour growth by cytokine and growth factor secretion. We propose in this application to: • further investigate key regulatory pathways by which tumour-secreted molecules promote vascularisation and inhibit immune cell function; • develop methods to inhibit tumour growth and metastasis by blocking vessel and tumour cell growth; • achieve tumour clearance by additionally promoting activation and homing of functional immune cells to the tumours. The project will comprise the collaboration of laboratories with complementary expertise. It will include experts in blood vessel and lymph vessel angiogenesis, metastasis formation, progenitor cell incorporation into tumours and tumour vessels, anti-tumour defence mechanisms of the immune system and viral transduction techniques. The final goal will be the preclinical evaluation of strategies in murine models of three of the most prevalent forms of human cancer, i.e. carcinomas of the breast, colon and prostate. The strategies to target the tumour will be based on gene, cell and immune therapy methods. They will include the use of: • adenoviruses for the expression of angiogenesis inhibitors following targeted delivery of the viruses to the tumour vasculature; • the genetic modification of murine embryonic and human umbilical cord/bone marrow progenitor cells and their directed homing into the tumour; • the use of genetically-engineered immune cell products or the transduction of immune cells to activate targeting of the tumours by innate and adaptive anti-tumour defence mechanisms. We expect that this project will contribute to innovation on three levels. Firstly, we will gain basic additional novel knowledge on important pathways and regulatory molecules for the recruitment of host cells to the tumours and their functional interaction with the tumour. Secondly, we will use this knowledge to test novel ways of targeting viruses and (transduced) cells to the tumours. Finally, we will evaluate whether, by a combination of anti-angiogenesis therapy with directed anti-tumour immunotherapy, it would be possible not only to inhibit tumour growth, but also to eradicate residual disease. Problem Despite significant improvements in diagnosis, surgical techniques, general patient care, and local and systemic adjuvant therapies, many solid tumours remain a major cause of death. Among the most prevalent and fatal forms are carcinomas of the breast, colon and prostate. Most deaths from cancer are due to metastases, seeded from the primary tumour via the blood and lymph vasculature, which are resistant to conventional therapies. The main barrier to the non-surgical treatment of the primary neoplasm and its metastases is the genetic instability and biological heterogeneity of cancer cells leading to the rapid development and growth of resistant cells. Since the expansion of solid tumours and their metastases beyond a minimal size is absolutely dependent on the formation of new blood vessels, anti-angiogenesis therapies constitute a promising alternative. In this case the genetically normal endothelial cells of the tumour vessels are targeted, avoiding the problem of resistance development. Furthermore, immune therapies are based on the ability of the immune system, evolved over evolutionary times, to cope with an almost unlimited number of antigens, thus opening the possibility to find a mechanism to target any tumour variant as long as the inhibitory milieu of the tumour environment can be overcome. Therefore angiogenesis and immune therapies remain among the most promising fields of cancer therapy. BIOLOGY 15
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: Keywords | Angiogenesis | vasculoge
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 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
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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
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.
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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