Cancer Research - Europa

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Micrometastasis in the bone marrow. Coordinator George N. Thalmann Dept. of Urology University of Bern Bern, Switzerland george.thalmann@insel.ch Partners Gabri van der Pluijm Leiden University Medical Center Leiden, The Netherlands Freddie Hamdy University of Sheffield Sheffield, United Kingdom Marc Colombel Philippe Clézardin INSERM University of Lyon Lyon, France 152 Manfred Hennecke Berthold GmbH & Co. KG Bad Wildbad, Germany Joel J. Niederhauser Fukuda Denshi Switzerland AG Basel, Switzerland Petra Zalud tp21 GmbH Saarbrücken, Germany David Deperthes Med Discovery S.A. Crans-près-Céligny, Switzerland Walter Pyerin Deutsches Krebsforschungszentrum Heidelberg, Germany Project number LSHC-CT-2006-018858 EC contribution € 4 034 200 Duration 48 months Starting date 01/04/2006 Instrument STREP Project website www.fp6-promet.net CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Keywords | Ewing’s sarcoma | EWS/FLI1 | CD99 | insulin like growth factor | microarrays | PROTHETS Prognosis and therapeutic targets in the Ewing family of tumours Summary The project through collaborative studies will defi ne prognostic markers and new therapeutic targets in the Ewing’s sarcoma family of tumours (ESFT) to provide rigorous scientifi c justifi cations for the development of clinical trials for this rare disease, which is mainly manifested in children. The main objective of this project is to evaluate the prognostic relevance of selected markers (EWS/FLI-1, secondary genetic alterations, CD99, IGF-IR, NOVH, erbB-2 and TTF1) and the eff ectiveness of therapeutic approaches targeting some of these molecules. Another major goal of the project is the construction of ESFT c-DNA microarrays and tissue arrays, which will be used for the analysis of diff erent histological subtypes of ESFT, primary and metastatic tumours and poor and good responders to chemotherapy. This will lead to: • the defi nition of forthcoming risk-adapted strategies and targeted molecular treatments to be advantageously combined with established therapies; • improved quality of life and survival for ESFT patients; • prevention of risk in groups at risk. Problem The Ewing’s sarcoma family of tumours (ESFT) includes: Ewing’s sarcoma; primitive neuroectodermal tumour; Askin’s tumour; paravertebral small-cell tumour; atypical Ewing’s sarcoma. ESFT represents a peculiar entity in oncology. In spite of its absolute rarity (about 300-400 cases per year in Europe), ESFT is one of the most frequent solid neoplasm in paediatric age groups. Due to this fact, its impact on the health system is particularly important. The adoption of multimodal treatments with very aggressive chemotherapeutic regimens have signifi cantly improved the chance of survival of ESFT non-metastatic patients, shifting the fi veyear survival rates to around 60 %. Despite these important clinical results, which are usually diffi cult to obtain in rare diseases, several problems related to histogenesis, prognosis and treatment response are still open. In particular: • the histogenesis of ESFT is still uncertain and the normal counterpart of ESFT cells is still unknown; • the lack of prognostic factors obliges the use of nondiff erentiated treatments for all patients, leading to overtreatment of those patients who could benefi t from less toxic therapies. The reduction of delayed side-eff ects is particularly important in this disease considering the young age of the patient and their long life expectancy; EARLY DETECTION, DIAGNOSIS AND PROGNOSIS • in the current state of ESFT treatment there is a survival ‘plateau’ (around 60 % for patients with localised disease and 25 % for highrisk groups) due to the lack of new drugs and toxicity that impedes more intense use of existing drugs. The identifi cation of new targets for innovative therapeutic strategies is, therefore, strongly needed for this tumour. Progress is generally hampered by the rarity of the disease (in Europe about 400 cases/year) implying a limited number of cases for eff ective research. Moreover, because ESFT is an orphan disease, no private company will develop new therapeutic tools and take on the costs to conduct pre-clinical investigation. Aim The project will defi ne prognostic markers and new therapeutic targets in the Ewing’s sarcoma family of tumours (ESFT) through collaborative studies to provide rigorous scientifi c justifi cation for the development of new therapeutic strategies for this rare disease, which is manifested for the most part in children. Goals expected to be achieved: • with respect to the problem of toxicity, the project, by identifying the clinical relevance of a number of markers, may allow the diff erentiation of patients in terms of risk to recur. This will enable more aggressive treatments where these are justifi ed, and avoid toxicity in cases where such treatments may be known to be unnecessary, with particularly signifi cant consequences for the quality of life of the patients; • successful treatment of therapy-resistant patients requires new strategies. Indeed, there is a desperate need for new therapeutic approaches in ESFT. A thorough study of the pre-clinical eff ectiveness of new targeted therapeutic strategies will be performed with the aim of the identifi cation of the Achilles’ heel in this disease and the consequent development of a tailored biological therapy to be used in association with conventional chemotherapy; • by providing an organisational framework for collaboration the project will also allow multi-centre collection and analysis of cases as well as suitable collaborative research to allow genetic studies for the screening of high-risk patients and patients responding diff erently to chemotherapy. Expected results • The identifi cation of prognostic factors in ESFT as a basis for the defi nition of individual therapeutic regimens, which would limit the incidence of acute side-eff ects and long-term morbidity as well as the economic and social consequences of intensive chemotherapy. • The defi nition of patient selection criteria to be used as a basis for beginning a pivotal clinical trial. • The creation of new therapeutic bullets against ESFT. They will be available at the end of the project as new drugs for ESFT treatment, together with the required toxicological 153
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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
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 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
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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
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Keywords | Ovarian cancer | thymidy
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Keywords | Quality assurance | clin
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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
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Keywords | Lymphoma | leukaemia | v
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Coordinator Riccardo Dolcetti Centr
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CCPRB Cancer Control using Populati
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EPCRC The European Palliative Care
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EUROCAN+PLUS Feasibility Study for
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EUSTIR A European strategy for the
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NORMOLIFE Development of new therap
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Scientifi c Model Systems The compl
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Performance of benchmarking exercis
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• markers correlating with the im
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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
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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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