Name:

Dr. Claude Malvy

Centre:

Centre National de la Recherche Scientifique

UMR8121 CNRS Institute Gustave Roussy PR2

Rue Camille Desmoulins

VilleJuif - France

Tel: +33 1 42115402    Fax: +33 1 42115245

e-mail: Cmalvy@igr.fr

Head of the research team: Artificial regulation of  gene expression by oligonucleotides localized within the research unit  UMR 8121 CNRS Vectorologie et transfert de gènes (Director: Dr Michel Perricaudet). This team has worked on antisense strategies since 1987.  The expertise of Claude Malvy has been until 1987  in anticancer agents and  DNA repair and then on small nucleic acids as potential pharmacological agents : antisense oligonucleotides, decoy oligonucleotides  and triple helix forming oligonucleotides. Since 2001 he has also been involved in studies with siRNAs. The delivery of these agents in vitro and in vivo has been one of the main goals of the research team.

Research group : Artificial regulation of gene expression by oligonucleotides.

Our group has been working on this strategy for the last 15 years. We indeed believe that oligonucleotides under various aspects can be more specific to treat cancer that the classical DNA binding drugs. We have been interested in decoys, antisense, triple helix forming, oligonucleotides. However oligonucleotides are already large molecules and therefore their cellular uptake in cells needs a great deal of attention. We have studied chemical vectors such as liposomes, peptides, polymeric nanoparticles. As targets we have been focusing during  the 4 last years on junction oncogenes. At the level of mRNA,  junction oncogenes offer indeed a very interesting target since the junction sequence is present only in the cancer cells. This is therefore an almost unique opportunity to have a very specific effet and therefore a lower toxicity for the treatment. Ewing sarcoma is exactly in this problematic and therefore the EWS-Fli-1 junction has been the center of our interest in these recent years. Untill now antisense oligonucleotides against various types of cancers have proved  a bit disappointing in clinical trials although many trials are still on. But siRNAs are very promising molecules with a very similar approach and we also work with siRNAs as potential therapeutic tools using our competences in this field.

Personnel involved in studies related to PROTHET's:

Jean Remi Bertrand, phD, Ingineer in INSERM (French medical research institute), has co-authored with C. Malvy all the international publications of the group related to oligonucleotides. He is very competent in molecular biology , cell culture, imaging and bio-informatics. He is also in charge of the monitoring of animal experiments.

Mireille Pottier, Technician from the Gustave Roussy Institute. She has a long practise of cell culture, cell transfection and study of various vectors with a potential for oligonucleotide and siRNA delivery.

Hind Elhamess. She is a 2nd year phD student studying the pharmacokinetics and biodistribution in mice of the oligonucleotide with potent inhibitory effect in vivo on EWS-Fli-1 expressing tumors. She will be supported by the Prothets program.

Marie Villemeur. She is a 1st year phD student. She studies the interactions between ifosfamide and the Ewing antisense oligonucleotide. She will interact with Dr Gottikh in Moscow for the study of new polymeric vectors for oligonucleotides. She will carry on experiments with the antisense oligonucleotide using human SKNMC Ewing cells in vitro and in vivo. She will study more precisely the action mechanism of the antisense oligonucleotide targeted against EWS-Fli-1. She will be supported by the Prothets program.

Ali Tamaddon, phD, is an iranian post doctoral student supported by Iran. Starting from january 15 2005 he will study the specificity of the EWS-Fli-1 antisense oligonucleotide by studying its effect on EWS and Fli-1 separately.

Two other phD students, Nedjma Toub and Henri de Martinprey are co-directed by Pr Couvreur in the Faculty of Pharmacy in Chatenay Malabry (University Paris-Sud 11) and are working on topics not related directly to our participation to the Prothets program.

Recent Publications relevant to the project:

G. Lambert, J.R. Bertrand, F. Subra, E. Fattal, H. Pinto-alphandary, C. Malvy, C. Auclair, P. Couvreur: EWS-Fli1 antisense nanocapsules inhibits primitive neuroectodermal tumor in mice. BBRC , 279, 401-406, 2000

A Maksimenko, C. Malvy, G. Lambert, J.R. Bertrand, E. Fattal, P. Couvreur: Particulate carriers are needed to inhibit tumor proliferation with antisense oligonucleotides. Pharmaceutical Research  20  10, 1565-1567, 2003

A. Maksimenko, G. Lambert, J.R. Bertrand, E. Fattal, P. Couvreur, C. Malvy. Therapeutic potentialities of EWS-Fli-1 mRNA-targeted vectorized antisense oligonucleotides. Annals of the New York Academy of Sciences. Vol 1002, 2003

A Maksimenko, P Couvreur , VPolard, J.R. Bertrand, M Aboubakar, M. Gottikh, C. Malvy. Antitumor effect of IV injected EWS-Fli-1 targeted vectorized antisense oligonucleotides in mice. Submitted for publication to British journal of Cancer.