Our team operates at the interface of chemistry and biology and pursues therapeutic innovation by identifying new anti-cancer targets as well as the development of new therapeutic compounds targeting either cell metabolism or cell invasion. At the present we focus on two families of compounds: the oxysterols, 7β-hydroxycholesterol and the phostines, a new family of compounds developed by our research consortium. These compounds are tested for antitumor activity and their mechanism of action are studied in in vitro and in vivo models of glioma. In that aim we have developed an innovative 3D culture system with biological properties that position it as relevant mechanistic tool to understand cancer cell invasion.

NB fig1

 

 

The nanofiber 3D culture system creates a tridimensional microenvironment convenient for GSC proliferation, adhesion and migration. In this environment, GSC form cellular extensions in various directions to attach to several fibres in a tridimensional manner.  Focal adhesion sites, visualized by anti-vinculin antibody staining, localize at the leading edges of the lamelipodia in 2D

 

 

As a result, glioblastoma cells treated with 7β-hydroxycholesterol appear to undergo energy stress as witnessed by the activation of AMP kinase and an increase in mitochondrial trans membrane potential followed by the collapse of the intracellular ATP concentration. A study of signalling pathways modified by 7β-hydroxycholesterol has been carried out and we are presently analysing 7β-hydroxycholesterol-induced glycolytic and mitochondrial energetic status modifications in order to understand carbon management by cancer cells. One of our short-term goals is to estimate the cross talk that might exist between metabolic and intra-cellular signalling pathways.

Phostines are analogues of both natural sugars and c-arylglycosides. They are obtained by a P-alkylation/transesterification reaction between a racemic H-phosphinate (P-chiral) and a furan-protected sugar. This leads to the formation of 4 diastomers.

 

 Bakalara Img2

 

 

Major publications

Hassani Z. et al., Mol Cancer Res. Oct;15(10):1376-1387, 2017
Guichet P.O. et al., Stem Cells. 33:21-34, 2015
Virieux D. et al., Top Curr Chem. 360:39-114, 2015
Babouri R. et al., Eur J Med Chem. Nov 2;104:33-41, 2015
Konan, K.M. et al., Sci Pharm. DOI: 10.3797/ 1307-08, 2014
Clarion L., et al., J Med Chem. 23;57(20):8293-306, 2014
de Weille J. et al., Biochem Pharmacol. Jul 1;86(1):154-60, 2013
de Weille J. et al., Biochem Pharmacol. Jul 1;86(1):161-7, 2013.

 

Valorization

New phosphorus containing heterocyclic compounds, sugar analogs, and compositions having anticancer activity containing the same. Pirat, J.-L., Virieux, D., Clarion, L., Volle, J.-N., Bakalara, N., Mersel, M., Montbrun, J., Cristau, H.-J., PCT Int. Appl. WO 2009004096 A1 20090108. WO 2009004096 (US 8383609 B2 granted February 26th 2013)

Hétérocycles phosphorés analogues de sucres à activité antimétastatique. Pirat, J.-L., Bakalara, N., Delaforge, Virieux, D., Volle, J.-N., M., Hugnot, J.-P., Lecouvey, M., Legrand, P., (Patent Fr 13 51654 filed 02-25- 2013)

Réseau tridimensionnel biocompatible et son utilisation en tant que support de cellules. D. Cornu, N.Bakalara, E. Marhuenda, A. Saleh. (Fr1851324 Fr 16 février 2018)

Joint Venture of Phost'in SAS in december 2014. Award and First Price Winner of the 16th National Contest for the creation of innovative technology companies

 

Collaborations

  • Prof. Jean-Luc Pirat – Prof. David Virieux  Institut Charles Gerhardt UMR 5253, Montpellier
  • Prof. David Cornu Institut Européen des Membranes UMR 5635, Montpellier
  • Prof. José Correa Basurto Instituto Politécnico Nacional, Mexico City (IPN)
  • Prof. James Dennis Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto

 

Fundings

INSERM/INCA. « Research Proposal in physics, mathematics and engineering sciences applied to the cancer research» : Glioma Track

SATT AxLR – Mécanisme d’action des phostines chez les gliomes et extaension à d’autres pathologies cancéreuses

REGION/INSERM – Identification de marqueurs de réponse aux phostines

SATT AxLR– Développement d’un système de culture 3D pour le criblage de molécules inhibant la migration des cellules cancéreuses

 

Contact

Bakalara Norbert