François GABORIAU, DR
– Molecular Pharmacology
– Cellular Biology
– Chemistry/Biology/clinical interface
Research topics and scientific objectives
– Development of iron chelators with antiproliferative activity
– Tumor vectorization by polyamines and their transport system.
– New Cancer therapy
– Iron depletion by chelators and neurodegenerative diseases
– Polyamines: emerging players in bacteria-host interactions
– Relationship between iron and polyamine metabolisms
Education and main positions held
In most cancerous cells, the need for a large increase in iron is linked to an acceleration of cell division and the deregulation of the subtle homeostasis of iron is one of many malfunctions that characterize these cells. A rise in the iron uptake (transferrin receptor), a fall in its export (ferroportin) and a disruption of its storage (ferritin) all result in an accumulation of iron which becomes highly available for DNA synthesis and thus activated cell proliferation.
In tumor cells, polyamine metabolism, including biosynthesis and uptake, is particularly amplified and the efficiency of the polyamine transport system (PTS) is greatly increased. This property of tumoral cells is of potential interest for targeting antitumor agents.
The activity of the group Quilamine is centered on the development of innovating targets in tumorogenesis and new ways of cellular entries for anticancer agents. In collaboration with the team of David Deniaud (CNRS UMR6230, Nantes) and that of Raphaël Tripier (CNRS UMR6521, Brest), we develop, at the interface of chemistry and biology, iron chelators coupled to a polyamine chain which plays the role of molecular taxi and specifically adresses the chelator into the tumor cell via its Polyamine Transport System (PTS). A first generation of Quilamine with a hydroxyquinolein moiety was prepared within the CEISAM unit (Nantes) and was biologically evaluated in our INSERM unit UMR991 in Rennes.
The very promising properties of this concept led us to protect it by a French patent (INPI n°1162108, 12/20/2011), followed by an extension PCT (PCT/FR2012/075907). Two funds of maturation from FEDER/Europe and the SATT OUEST-Valorization enabled us to demonstrate the proof of this concept in animals and to initiate the preclinical study of the most active Quilamine HQ1-44, in various models of tumours as well as the study of its biodisponibility and its metabolism.
In association with a polyamine-depleted diet and an inhibitor of the biosynthesis of these molecules (DFMO), Quilamine HQ1-44 (15 days i.p 40mg/kg) inhibits more than 80% the growth of tumours (human colon adenocarcinoma cells, HCT116), xenografted in immunocompromised nude mice. This treatment without side-effect like those observed with salts of platinum, the reference treatment for this kind of cancer, could constitute an effective therapeutic alternative to the treatment of cancers characterized by an activation of the STP. (technological supply Ouest-Valorization, http://technologies.ouest-valorisation.fr/)