Objective
Ovarian cancer is the fifth most common cause of death from cancer in women. The standard firstline treatment is a combination of paclitaxel and carboplatin (DDP) or carboplatin alone. Age, performance status and treatment preferences of the individual patient help in selecting single or combination therapy. In the case of progressive disease or drug resistance treatment with platinum, either alone or in combination, especially investigational compounds should be used. Themechanisms behind acquired resistance to cDDP and its derivatives are not clear yet, although it is evident that the process is multifactorial including, enhanced DNA repair. In the human ovarian carcinoma cell line A2780, a 3-fold-DDP-resistance was associated with cross-resistance to the thymidylate synthase (TS) inhibitor 5-fluorouracil and to methotrexate, a 2.5-fold increase in TS, and an increase in the intracellular pools of the TS cofactor 5, 10-methylentetrahydrofolate and of tetrahydrofolate. The ultimate goal of LIGHTS is to directly halt tumour progression and the development of drug resistance upon treatment with platinum derived drugs by inhibiting the protein regulatory function of monomeric TS through small molecule cellular perturbation. The scientific and technological objectives will be to design small-ligand libraries to bind to the TS monomer (dimer interface) and thereby disrupt TS.
The strategy will include, protein system analysis, protein labelling to identify low-affinity ligands, peptide mimic design & synthesis, and filtering for ADME properties. The multidisciplinary approach will be carried out by a consortium integrating Molecular modelling, Chemistry, Chemoinformatics, Structural Biology and Pharmacology, and will apply the knowledge being created by genomics and other fields of basic research the problem of discovery of anticancer agents. The consortium consists of six groups from five different countries, including three SMEs.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural scienceschemical sciencesinorganic chemistrytransition metals
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistance
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesmolecular biologystructural biology
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Call for proposal
FP6-2005-LIFESCIHEALTH-7
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Funding Scheme
STREP - Specific Targeted Research ProjectCoordinator
MODENA
Italy