Cancer Research - Europa

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Immunogenicity testing model. Coordinator Norman J. Maitland YCR <strong>Cancer</strong> research Unit (Area13) Dept. of Biology University of York York, United Kingdom njm9@york.ac.uk Partners Chris H. Bangma Dept. of Urology Erasmus MC Rotterdam, The Netherlands h.j.vanalphen@erasmusmc.nl Thomas Totterman Clinical Immunology Division Rudbeck Laboratory Uppsala University Uppsala, Sweden thomas.totterman@klinimm.uu.se Leonard Seymour Dept. of Clinical Pharmacology Radcliffe Infirmary University of Oxford Oxford, United Kingdom len.seymour@clinpharm.ox.ac.uk Rob Hoeben Dept. of Molecular Cell Biology Leiden University Medical Center Leiden, The Netherlands r.c.hoeben@lumc.nl 208 Stefan Kochanek Division of Gene Therapy University of Ulm Ulm, Germany stefan.kochanek@medizin.uni-ulm.de Karel Ulbrich Dept. of Biomedicinal Polymers Institute of Macromolecular Chemistry Academy of Sciences of Czech Republic Prague, Czech Republic ulbrich@imc.cas.cz Leif Lindholm Gotagene AB, Holtermansgatan 1B Stena Center Goteborg, Sweden leif.lindholm@gotagene.se Wytske van Weerden Scuron Rotterdam, The Netherlands weerden@scuron.com Alan Raymond Pro-Cure Therapeutics Ltd Biocentre York, United Kingdom alan.raymond@pro-curetherapeutics.com Ernst Wagner Centre for Drug <strong>Research</strong> Dept. of Pharmacy Pharmaceutical Biology – Biotechnology Munich, Germany ernst.wagner@cup.uni-muenchen.de Jean-Paul Behr Laboratorie de Chimie Génétique Unité Mixte CNRS & Université Louis Pasteur de Strasbourg Faculté de Pharmacie Illkirch, France behr@bioorga.u-strasbg.fr Patrick Erbacher Polyplus Transfection Bioparc Illkirch, France perbacher@polyplus-transfection.com Kerry Fisher Hybrid Systems Ltd Upper Hayford, United Kingdom kerry.fisher@hybridsystemsltd.co.uk Project number LSHB-CT-2004-512087 EC contribution € 9 683 102 Duration 60 months Starting date 01/01/2005 Instrument IP Project website www.giant.eu.com CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Keywords | Dependence receptors | apoptosis | tumour suppressor | HERMIONE Novel Anticancer Therapeutics based on Modulation of Apoptosis through Dependence Receptors Summary Receptors are usually seen as inactive unless bound by their ligand. However, a new concept has emerged since 1998, by which some receptors can in fact mediate two diff erent signalling pathways, depending on the presence or absence of their ligand. Studies of such receptors have indeed revealed that, in the absence of ligand, signalling initiates an active process leading to cell death via apoptosis, whereas programmed cell death is inhibited in the presence of the ligand. Therefore, expression of these receptors leads to a state of cellular dependence on their respective ligands, which is why they have been named ‘Dependence Receptors’ (DRs). The diff erent DRs trigger apoptosis in the absence of ligand, suggesting that they may all act as regulators of tumourigenesis. In addition, expression of DRs is lost or decreased in many tumours, suggesting that they act as tumour suppressors and that their loss represents a selective advantage for tumour cells. HERMIONE proposes that unravelling the link between different DRs (DCC, UNC5H, KAI1 and RET), downstream molecules and apoptosis will lead to the identifi cation of new potential targets for anti-cancer drugs. The project will provide a better understanding of the signalling pathways acting downstream of DRs, observe the association of mutations with the onset and progression of tumours (grade, prognosis), and generate murine models in which the apoptotic signalling of the DR is turned off to study the implication of DRs in tumourigenesis in vivo. Through this, HERMIONE will generate knowledge on DR-signalling pathways involved in the apoptosis of tumoural cells (colorectal, breast, thyroid and prostate cancers) and use the general concept of Dependence Receptors to select and perform pre-clinical testing of novel anti-cancer drugs. Problem Colorectal, breast and prostate cancer are among the commonest forms of cancer in Europe. Breast cancer is the main cause of death by cancer, killing over 400 000 women a year. There is no effi cient treatment against metastatic breast tumours and available anti-cancer treatments are imperfect, therefore the probability of cure is not high. Existing treatments are highly toxic to normal tissue and cause substantial loss of life quality. Surgery, chemotherapy and radiotherapy TREATMENT are very invasive, and advanced stage cancer patients treated with cytotoxic therapeutics are often subject to debilitating side- eff ects. Therefore, there is a great need to develop more precise therapeutics, to reduce side-eff ects and improve the overall wellbeing of treated patients. Aim The aim of HERMIONE is to understand better how dysfunctions in DR-signalling can lead to tumour formation and/or progression. The generated knowledge will be applied to the development of targeted drugs, to provide safer and more eff ective treatments for patients. The following models, by which DRs regulate tumour initiation, progression and metastasis, can be surmised from current knowledge on DR-signalling and illustrate the project’s hypothesis that these receptors act as tumour suppressors via their pro-apoptotic activity: in a normal context: the receptor is bound by its ligand and induces a positive signal (survival, diff erentiation, etc.). In the case of genetic alteration leading to cell transformation and thus cell proliferation, the concentration of ligand in the extracellular environment becomes insuffi cient to bind all receptors. In some cases, cells acquire the property to migrate into the blood circulation and/or invade other tissues where the ligand is absent. Unbound dependence receptors consequently trigger apoptosis. According to these models, a selective advantage for a tumour cell would be to lose the death activity of DRs by mutation, to curb their expression or to acquire autocrine expression of the ligand. Therefore, Dependence Receptors appear to be original targets for combating cancer and potential candidates to be studied in the aim of developing novel cancer therapeutics. In order to achieve this, proper understanding of the way these receptors induce apoptosis, i.e. deciphering the signalling pathways operating downstream, is of great importance. Expected results • Understanding the fundamental phenomena: • to yield better understanding of the signalling pathways that act downstream of dependence receptors. Understanding the way Dependence Receptors are linked to the trigger of apoptosis will provide targets for drug development; • to analyse the status of DR/ligand pairs in human tumourigenesis: is there a selective advantage to losing expression of the receptor, gaining autocrine expression of the ligand or losing death function by mutation? From these studies, clear links between DRs and tumour progression will be established, thereby generating new markers for prognosis. 209
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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
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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
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: Keywords | Gene therapy | adenoviru
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
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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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