Cancer Research - Europa

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Coordinator Hans E. Johnsen Aalborg Hospital, Aarhus University Hospital Dept. of Haematology Aalborg, Denmark h.e.johnsen@dadlnet.dk Partners Karin Vanderkerken Vrije Universiteit Brussel Brussels, Belgium Kvdkerken@vub.ac.be Pieter Sonneveld Erasmus University Medical Center Rotterdam, The Netherlands p.sonneveld@erasmusmc.nl Alberto Orfao University of Salamanca Salamanca, Spain orfao@usal.es 56 Surinder S. Sahota School of Medicine Southampton, United Kingdom Nico A. Bos University Medical Center Groningen, The Netherlands n.a.bos@med.umcg.nl Bernhard Klein University of Montpellier Montpellier, France klein@montp.inserm.fr Dirk Hose University of Heidelberg Heidelberg, Germany Dirk.Hose@med.uni-heidelberg.de Zojer Niklas Wilheminenhospital Wien, Austria niklas.zojer@wienkav.at Project number LSHC-Ct-2006-037602 EC contribution € 2 734 000 Duration 36 months Starting date 01/11/2006 Instrument STREP Project website www.myelomaeurope.org CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Keywords | p53 tumour suppressor | mutations | gain-of-function | p53 status | clinical outcome | mutant p53-reactivating drugs | novel cancer therapy | Mutp53 Mutant p53 as a target for improved cancer treatment Summary Mutations in the p53 tumour suppressor gene are the most frequent genetic alteration in human cancer, occurring in over 40 % of all cases of cancer. One well-studied outcome of these mutations is the loss of the tumour suppressor activity of the wild type (wt) p53. However, there is growing evidence that many of the mutations that occur in the p53 protein generate mutant p53 proteins (mutp53) have acquired new biochemical and biological properties. Through this gain of function (GOF), mutp53 is believed to contribute actively to the cancer process. We propose to explore mutp53 as a target for novel anticancer therapies. Such therapies should aim to either abrogate the GOF eff ects of mutp53, or restore wt-like properties to mutp53, so that it can now regain its tumour suppressor capabilities. A multi-disciplinary approach will be undertaken to explore and exploit the contribution of mutp53 to cancer. One component of this project will investigate in depth the molecular properties of mutp53: structural studies will pinpoint the changes that particular mutations infl ict on the structure of p53, and allow the classifi cation of mutp53 into distinct subclasses. In parallel, biochemical studies will explore the mode of action of mutp53 within cells, including its impact on patterns of gene expression, identifi cation of specifi c DNA sequences targeted by mutp53, and discovery of mutp53-interacting cellular proteins. Preclinical models for mutp53-driven cancer will also be developed, as a critical instrument for pre-clinical studies. The other component will aim at translating this wealth of information into better cancer therapy. One avenue will address the clinical relevance of particular p53 mutations in human cancer, particularly its impact on the patient’s response to chemotherapy. This should lead to guidelines for more eff ective use of conventional therapy. The other avenue will explore novel therapies targeted at mutp53 and mutp53-expressing tumour cells. A major eff ort will focus on the discovery of small compounds that can restore wtp53-like activity to mutp53. An innovative approach to immunotherapy directed against mutp53-overexpressing cancer cells will also be explored. Owing to the extremely high frequency of p53 mutations, the success of this project will impact on a very large number of cancer patients in Europe and worldwide. BIOLOGY Problem Cancer is a major cause for human suff ering in Europe as well as elsewhere in the world. It causes immense eff ects on the cancer patients themselves, on their families, as well as on society at large. In addition to the severe human suff ering and their immediate societal impact, cancer treatment and management is also a major economic burden. The importance of this problem and the urgency of the need for novel approaches to cancer management and treatment have been recognised by the EC, as refl ected by the establishment of a specifi c call in the area of ‘Combating Cancer’. Mutations in the p53 tumour suppressor gene are the most frequent genetic alteration in human cancer, occurring in over 40 % of all cases of cancer. We propose to explore mutp53 as a target for novel anticancer therapies. Such therapies should aim to either abrogate the gain of function (GOF) eff ects of mutp53, or restore wt-like properties to mutp53, so that it can now regain its tumour suppressor capabilities. A multi-disciplinary approach will be undertaken to explore and exploit the contribution of mutp53 to cancer. Aim In our proposed project, we introduce a multidisciplinary approach to explore mutp53 as a new target for innovative treatment. A primary objective of the ‘Combating Cancer’ initiative is ‘to combat cancer by developing improved patient-oriented strategies… to better treatment with minimal side-eff ects’ with a focus on ‘encouraging the development of evidencebased guidelines for good clinical practice’. Our project meets these requirements in at least two distinct ways: • We aim to improve the use of contemporary chemotherapy through providing better guidelines based on correlations between p53 genotype of the tumour and its response to particular types of anti-cancer drugs. It is important to keep in mind that, although novel therapeutic approaches are very exciting and promising, millions of cancer patients all over Europe are being treated every day with standard chemotherapy. Beyond its limited effi cacy, this is also associated with signifi cant toxicity and therefore often unjustifi ed patient suff ering. The ability to make better predictions as to which particular chemotherapeutic regimen is most likely to work for a particular patient thus has far-reaching implications, both in ensuring better and more eff ective treatment and, not less importantly, in preventing unnecessary suff ering from severe side-eff ects in cases where it is clear that a particular treatment is not going to work. 57
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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
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 and 54: Keywords | Mitosis | phosphorylatio
Page 55 and 56: Keywords | Therapy | genome | telom
Page 57: Keywords | Multiple myeloma | cance
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
Page 105: 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
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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
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Coordinator Robert Hawkins Universi
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Expected results The BACULOGENES pr
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descriptors of the molecules to be
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Keywords | Therapeutic vaccine | im
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Keywords | Cancer chemotherapy | dr
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Keywords | Children | cancer | leuk
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Chimaeric TCR shown in context of n
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Andrea Splendiani Leaf Bioscience s
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Coordinator Anne O’Garra The Medi
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Coordinator Jacques Bartholeyns IDM
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Structure Driven Drug Design The in
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• acquire fundamental knowledge a
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Terry Jones Victoria University of
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Potential applications The use of t
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groups and management structures. T
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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
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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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HOW TO OBTAIN EU PUBLICATIONS Our p
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