Cancer Research - Europa

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NORMOLIFE Development of new therapeutic substances and strategies for treatment of pain in patients with advanced stages of cancer Summary Keywords | Cancer pain | analgesic medicines | pain pharmacology | Prolonging the life expectation of patients with advanced cancer could be done by modern medicine. However, progressive pain that is associated with progression of the disease is the major factor that destructs the last moments of life. Severe progressive and uncontrolled pain is a major reason of requesting euthanasia. The applications of oral (morphine) pills or transdermal patches with lipophilic analgesic drugs are the most common treatments of cancer pain. These compounds penetrating into central nervous system produce side eff ects (respiratory depression, constipation, tolerance, sedation, etc.) to such extent that pain treatment is reduced by doctors or refused by the patients. The discoveries of the last years indicated the changes in expressions of pro- and antinociceptive receptors in pathologically changed peripheral tissues as well as in the central nervous system. The concerted modulation of these receptors in combination with designed receptor ligands may block nociceptive signal formation and transmission more eff ectively than traditional monotherapies. The objective of this project is to focus on the development of new multitarget compounds and methods which will interact with opioid receptors expressed in infl amed and/or pathologically modifi ed tissues. Partial penetration into the central nervous system will result in synergistic pain suppression via interaction between the peripheral and central nervous system. Alternatively, newly developed compounds could be applied directly into central nervous system to interact with the specifi c, pathological set of receptors. The developed compounds will be screened in vitro in a cell silicon hybrid biosensor and selected compounds, in vivo in rodent’s cancer pain models. The project will yield new basic data on structural requirements of analgesics for treatment of persistent cancer pain in advanced stages and will develop new compounds characterized to the stage that will allow to promote them for further clinical phase testing. Problem The approach in which compounds are designed to interact with a wide spectrum of targets involved in pain signal formation and transmission is a new and original therapeutic strategy, opposite to current strategies that use drugs which are as receptor-selective as possible. The project’s major goal is chemical design of new multitarget molecules and analysis of their pharmacological properties that will result in the selection of several new compounds for further clinical evaluation as a new generation of potent analgesics for multicomponent cancer pain treatment. Aim The project will involve three general complementary scientifi c objectives: chemistry, in vitro biopharmacology and in vivo pharmacology that will be accomplished by multidisciplinary teams integrated in the project. Synthesis of new compounds, designed by theoretical (SAR) analysis, will be synthesized in chemical laboratories. Hundred new compounds will be designed and synthesized on initial stages of the project. These compounds will be preselected in in vitro tests. The in vitro tests comprise receptor affi nity evaluation and functional cell-based assays. The selected (expected 6) compounds will be fi nally characterized in vivo in an animal model of cancer pain. Expected results The application of a new generation of medicines designed under the NORMOLIFE project will reduce side eff ects generated by traditional opioids in central nervous system, including tolerance, dependence, constipation, euphoria, etc. The major prospective application of the results will be a more eff ective treatment of acute as well as chronic, neuropathic and infl ammatory cancer pain of patients with advanced stages of the disease. We predict that the project will be able also to defi ne the diff erences between the spectrum of pain symptoms and pain progression in progressive cancer typical for female (ovarian) and male (prostate) patients. The establishment of such diff erences will help to propose diff erent pain treatment for women and men. Potential applications The experimental preclinical data of the newly-developed compounds will allow for selection and proposition of new medicines for further clinical evaluation. 240 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Nerve cells cultured on a micro-electrode chip for testing analgetics. (Foto C. and M. Kage) Coordinator Andrzej W. Lipkowski Medical Research Centre Polish Academy of Sciences Warsaw, Poland andrzej@lipkowski.org Partners Giuseppe Ronsisvalle Faculty of Pharmacy University of Catania Catania, Italy Dirk Tourwe Free University of Brussels Brussels, Belgium Aleksandra Misicka-Kesik Warsaw University Warsaw, Poland Geza Toth Biological Research Centre Hungarian Academy of Sciences Szeged, Hungary Zafiroula-Iro Georgoussi Institute of Biology National Centre of Scientific Research ‘Demokritos’ Athens, Greece Zofia Lipkowska Institute of Organic Chemistry Polish Academy of Sciences Warsaw, Poland Wieslawa Walisiewicz-Niedbalska Industrial Chemistry Research Institute Warsaw, Poland Dieter G. Weiss University of Rostock Rostock, Germany Olaf Schroeder Pattern Expert Borsdorf, Germany Frank Graage Steinbeis-Forschungs- und Entwicklungs-zentrum GmbH Rostock, Germany CANCER CONTROL, SURVIVORSHIP AND OUTCOMES RESEARCH Project number LSHC-CT-2006-037733 EC contribution € 2 182 325 Duration 36 months Starting date 01/12/2006 Instrument STREP Project website www.normolife.eu 241
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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
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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
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 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
Page 240 and 241: EUSTIR A European strategy for the
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
Page 261 and 262: Lingner, Joachim 54 Linial, Michal
Page 263 and 264: Ragno, Pia 115 Rainford, Martyn 92
Page 265 and 266: Vernos, Isabelle 22 Veronesi, Umber
Page 267 and 268: ● 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: HOW TO OBTAIN EU PUBLICATIONS Our p
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