Cancer Research - Europa

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DEPPICT Designing Therapeutic Protein-Protein Inhibitors for Brain <strong>Cancer</strong> Treatments Summary Keywords | Protein-Protein interactions | small molecule inhibitors | knowledge driven drug design | blood/brain | tumour penetrant | Protein-Protein interactions (PPI) are central elements in cellular processes and important targets for selective therapeutic agents. They constitute a rich area for discovery of novel small ligand-based therapies. This proposal seeks to utilise such interactions, in particular those featuring a a-helix binding groove such as p53-MDM2, or more novel targets, e.g. nm23-prune, to develop targeted small-molecule libraries with physico-chemical properties appropriate for therapeutic eff ect against various tumour types such as the brain cancers of glioblastoma and medulloblastoma. Combination of the concepts below should provide an opportunity to unlock the potential of protein interactions as key components in signalling pathways via design of selective small-molecule modulators targeting the kinaseeff ector interaction instead of the ATP active site. • Develop an understanding of the elements controlling selectivity in Protein-Protein signalling networks by developing approaches for design of small molecules that target a-helix binding groove interactions through use of structure-based and fragment-based approaches. • Data-mining of ADME and drug-drug interactions to build a predictive database for library design. • Develop quantitative structure/property relationships, with an emphasis on CYP-mediated metabolism, ABC transporters at the blood/brain and brain/tumour interfaces, mutagenicity, solubility, pKa, and passive permeability, and predictive tools for mutagenicity and other genetic toxicology end-points. • Develop predictive PK and PBPK models to improve understanding of BBB and tumour penetration. • In vitro and in vivo PK/PD and TK/TD characterisation of compounds, to increase understanding of their mechanism of action and reduce the use of laboratory animals. Such knowledge-based approaches will also be applicable to design of small molecules for other Protein-Protein interactions utilising a a-helix binding groove both for peripheral tumours and other therapeutic areas. Problem Amongst the range of cancer types, brain and perhaps pancreatic cancers are especially lacking in eff ective treatments. In particular brain tumours are: • the leading cause of death from childhood cancers among persons under 19; • the second leading cause of cancer-related deaths in males aged 20-39; • the fi fth leading cause of cancer-related deaths in women aged 20-39. Although onset of disease varies with tumour type, it can occur at a relatively young age causing additional and signifi cant social and economic problems for both patients and their families. Current standard treatments include surgery, radiation therapy and chemotherapy. These may be used either individually or typically in combination. Brain cancers however present unique problems due to the location of the tumours: surgery and radiotherapy carry considerable risk to the patient and resection is not always possible. Chemotherapy is faced with the problem of penetration of drugs across the blood-brain barrier (BBB) and of lack of specifi city. The focus for these patients is therefore on more eff ective therapies to prevent relapse, and on more effi cient screening and diagnosis to halt the disease at an early stage. Aim The main objective of the proposed project is to provide more eff ective anti-tumour therapies by developing targeted small ligand libraries with appropriate physico-chemical properties for therapeutic eff ect targeted against Protein- Protein interactions implicated in various tumour types. The research activities will concentrate on knowledge-based approaches supporting translational research aimed at bringing basic knowledge through to applications in clinical practice and public health. The project will thus focus on providing small molecule ligands with minimal side eff ects as treatments for the brain tumours glioblastoma (GBM) and medulloblastoma. Expected results The successful integration of the various aspects of this proposal will provide a robust knowledge-based strategy for exploiting Protein-Protein interactions as drug targets in the treatment of brain tumours. The strategy should however be suffi ciently generic to be transferable to other disease areas, especially within the CNS, where Protein-Protein interactions provide an entry point into disease-modifying therapies. 188 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Structure Driven Drug Design The individual components needed to achieve successful knowledge driven drug discovery will be combined to harness the opportunity for Protein-Protein inhibitors as potential small molecule therapies for brain tumours. Potential applications The design of selective small molecule modulators of Protein-Protein interactions should provide the basis for developing new therapeutic strategies against brain cancers. They will allow for improving current libraries and for building predictive databases for library design of new specifi c drugs and therapeutic agents with high central nervous system penetration, necessary to reach a higher effi cacy, selectivity, responsiveness and lower toxicity. In addition these approaches will represent a powerful system for preclinical data collection, leading to an optimisation of clinical trials setting and development. TREATMENT Predictive ADME and Drug-Drug Interactions Protein-Protein Interaction Inhibitors Quantitative Structure/Property Relationships Predictive PK & PBPK Models In vitro and in vivo PK/PD and TK/TD Characterisation Coordinator Graeme Robertson Siena Biotech SpA Siena, Italy grobertson@sienabiotech.com Partners Gabriele Cruciani Molecular Discovery Pinner Middlesex, United Kingdom Massimo Valoti University of Siena Siena, Italy Project number LSHC-CT-2007-037834 EC contribution € 3 640 293 Duration 36 months Starting date 01/03/2007 Instrument STREP – SME Project website www.deppict.eu Juan Aymami Crystax Barcelona, Spain Roberto Pellicciari University of Perugia Perugia, Italy Sophie Ollivier Aureus Pharma Paris, France Herbie Newell University of Newcastle Newcastle, United Kingdom 189
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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
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 154 and 155: 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: Coordinator Jacques Bartholeyns IDM
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
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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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