Cancer Research - Europa

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Coordinator Jan-Michael Peters Forschungsinstitut für Molekulare Pathologie Gesellschaft m.b.H. Vienna, Austria peters@imp.univie.ac.at Partners Jan Ellenberg European Molecular Biology Laboratory Heidelberg, Germany jan.ellenberg@embl-heidelberg.de Roland Eils Deutsches Krebsforschungszentrum Heidelberg, Germany r.eils@dkfz-heidelberg.de Frank Sieckmann Leica Microsystems CMS GmbH Mannheim, Germany frank.sieckmann@leica-microsystems.com Tony Hyman Max-Plank-lnstitut für Molekulare Zellbiologie und Genetik Dresden, Germany hyman@mpi-cbg.de 52 Gary Stevens Gene Bridges GmbH Heidelberg, Germany gary.stevens@genebridges.com Andrea Musacchio European Institute of Oncology Milan, Italy andrea.musacchio@ieo-research.it Ariane Abrieu Centre National de la Recherche Scientifique Montpellier, France ariane.abrieu@crbm.cnrs.fr Tim Hunt Clare Hall Laboratories, Cancer Research UK South Mimms, United Kingdom tim.hunt@cancer.org.uk Kai Stoeber University College London London, United Kingdom k.stoeber@ucl.ac.uk Richard Durbin Genome Research Limited Wellcome Trust Sanger Institute Cambridge, United Kingdom rd@sanger.ac.uk Project number LSHG-CT-2004-503464 EC contribution € 8 578 177 Duration 48 months Starting date 01/04/2004 Instrument IP Project website www.mitocheck.org CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Keywords | Therapy | genome | telomerase | diagnosis | drugs | MOL CANCER MED Developing molecular medicines for cancer in the post-genome era Summary The cellular immortality enzyme telomerase (one of the most promising universal cancer markers) and associated telomere maintenance mechanisms represent novel anti-cancer targets of enormous therapeutic and diagnostic potential. In MOL CANCER MED, a multinational EU translational cancer research consortium has been established, in which expert cancer geneticists and molecular biologists will interact with prominent pharmacologists, clinicians and pathologists to develop these exciting new cellular targets into measurable pre-clinical advances, within a four-year time-frame. The project has been structured into three, highly interactive areas of activity, involving the fundamental evaluation and pre-clinical validation of: • telomerase as a target for cancer treatment and diagnosis based on new molecular knowledge about its expression and function; • associated downstream telomere maintenance mechanisms as additional targets for novel drug design; • new anti-cancer drugs based on these targets. The consortium will bring to bear diverse and complementary technological know-how of considerable power to deliver the above primary objectives. Eff ective management will maximise synergies across MOL CANCER MED in order to produce genuine improvements in the design of new treatments that promise to be active against a broad spectrum of common human malignancies. Problem Cancer is a leading cause of death in the western world, second only to cardiovascular disease, and is therefore a European public health problem of overwhelming human and economic signifi cance. The incidence of cancer is set to increase substantially with demographic and possibly environmental infl uences playing a part. However, there is now an improved molecular understanding of the key genetic, biochemical and cellular changes leading to cancer, in signifi cant part due to the eff orts of diverse groups of world-class EUbased scientists. With the completion of the human genome sequence imminent, it is now timely to initiate a major European coordinated eff ort to translate fundamental scientifi c knowledge about cancer into safer, more eff ective, therapies and improved early diagnostic procedures. MOL CANCER MED is focused on a single group of highly promising anti-cancer targets associated with telomerase BIOLOGY and telomere maintenance. Repression of telomerase in the somatic tissues of humans, and probably other long-lived mammals, appears to have evolved as a powerful protective barrier against cancer. Immortalisation in vitro of normal human cells that lack telomerase involves the reactivation of telomerase or, rarely, an alternative (ALT) mechanism for maintaining telomeres. It is clear that telomerase is obligatory for continuous tumour cell proliferation, clonal evolution and malignant progression. Because telomerase is found in around 90 % of human cancers and is essential for the continued proliferation (and clonal evolution) of cancer cells, it represents one of the most exciting anti-cancer targets thus far discovered. Results with a variety of telomerase inhibitory strategies in human cancer cells have confi rmed that its functional inactivation results in progressive telomere shortening, leading to growth arrest and/or cell death through apoptosis. Promising candidate small molecule inhibitors are beginning to emerge that will form the basis for anti-telomerase drug development. MOL CANCER MED is based on successful Framework 5 research concerned with establishing the value of the cellular immortality enzyme telomerase as an anti-cancer target (Project: QLG-1999-01341; TACIT) and represents an expansion and elaboration of this. TACIT yielded results that have triggered new translational research with clearly defi ned clinical applications. To this set of activities have been added carefully selected new EU research teams, notably in the area of drug development. Aim The principal aim of MOL CANCER MED is to fully exploit the results of recent fundamental advances in understanding the role of telomerase and telomere maintenance mechanisms in human cancer development, in order to achieve genuine clinical benefi t (i.e. in developing both improved diagnostics and anti-cancer therapies). The principal measurable objectives of the project, over the complete 48 months period, are: • to validate further the potential of telomerase and telomere maintenance systems in cancer therapy and diagnosis; • to identify novel molecular targets based on telomere structure, function & stability, that may be of value in treatment and diagnosis of the common human cancers; • to create a programme of novel small molecule drug development based initially on recently identifi ed (but thus far poorly exploited) targets and, later (from month 12 onwards) exploiting completely new targets identifi ed during the project. Expected results • Novel anti-cancer drug targets and diagnostic methodologies derived from advances in: • the understanding and defi nition of biochemical response pathways underpinning the telomere checkpoint for somatic cell proliferation; 53
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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 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: Keywords | Mitosis | phosphorylatio
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
Page 99 and 100: Prevention The fact that preventing
Page 101 and 102: Coordinator Elio Riboli Imperial Co
Page 103 and 104: 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
Page 124 and 125:
Coordinator John A. Foekens Dept. o
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124 Aim Drop-Top has two major obje
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Coordinator Gorka Ochoa Progenika B
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Expected results The E.E.T.-Pipelin
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e developed by eTUMOUR is likely to
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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
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P-MARK Validation of recently devel
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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
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Coordinator Raffaella Giavazzi Isti
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• Development of tools for diagno
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Treatment Two major problems when t
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Coordinator Lluis M. Mir UMR 8121 C
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Potential applications ANGIOSTOP ha
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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
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Chimaeric TCR shown in context of n
Page 185 and 186:
Andrea Splendiani Leaf Bioscience s
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Coordinator Anne O’Garra The Medi
Page 189 and 190:
Coordinator Jacques Bartholeyns IDM
Page 191 and 192:
Structure Driven Drug Design The in
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• acquire fundamental knowledge a
Page 195 and 196:
Terry Jones Victoria University of
Page 197 and 198:
Potential applications The use of t
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groups and management structures. T
Page 201 and 202:
T. Barbui Azienda Ospedaliera-Osped
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Keywords | Mantle cell lymphoma | t
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Keywords | Hypoxia | HIF | pericell
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Keywords | Radiation-induced compli
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Keywords | Gene therapy | adenoviru
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Keywords | Dependence receptors | a
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Keywords | Photodynamic therapy | a
Page 215 and 216:
Keywords | Ovarian cancer | thymidy
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Keywords | Quality assurance | clin
Page 219 and 220:
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
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
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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
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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