CV Science

Norbert Bakalara PhD Biological Chemistry and Molecular Biology

Course and current status

Norbert Bakalara is graduated from the Pasteur Institute (virology option directed by Luc Montagnier, class of 1983). He started his scientific career in the CNRS laboratory (Laboratoire de Biologie et de la Differenciation Cellulaire directed by Y. Thouveny) at the University of Marseille Luminy. In 1987 he defended his phD on the cloning of genes involved in the regeneration of an “annélide polychète” : Owenia fusiformis. Then he has been working for 18 years in parasitology including 7 years abroad. He joined in 1986 for a first post-doc the laboratory of Jose-Luis Saborio at the CINVESTAV del IPN in Mexico DF working on oncogenes expression in Trypanosoma cruzi. In 1987 he moved to UCLA in the laboratory of Larry Simpson where he participated to the discovery of the RNA editing process in kinetoplatidae. With an assistant professor position he worked from 1989 to 1991 on  gene transcription regulation in Trypanosome brucei at the de Duve institute in Brussels (ICP-TROP unit directed by Fred Opperdoes). He came back to France in 1991 to be appointed as an assistant professor and the University Victor Segalen in Bordeaux. He started in the CNRS UMR 5016 of Theo Baltz the development of phosphorous derivates (bisphosphonates) as therapeutic molecules against trypanosomatids. Later on in 2004 he obtained a position as professor of biochemistry in the graduate chemistry scholl of Montpellier (ENSCM) where he pursued to develop phosphorous derivates (phosphinolactone) as anti-tumoral and anti-kinetoplastidae compounds. He also initiated a research project on the mode of action the 7-beta hydroxycholesterol in glioblastoma cells proliferation and death.

Scientific summary

Norbert Bakalara’s research interests are focused on the discovery of cellular and molecular mechanisms activated during a pathological process, to identify, from this mechanisms, pharmacological targets and to design drugs against these targets.

• Discovery of guide RNA guiding RNA editing in trypanosomatids

A majority of mitochondria maxicircle transcripts cannot be translated into proteins due to multiple frameshifts in the sequences. These frameshifts are corrected after transcription by the insertion and deletion of uridine residues at precise sites which create an open reading frame that is translated into a mitochondrial protein homologous to mitochondrial proteins from other cells. Norbert Bakalara participated to the discovery of guide RNA and the molecular mechanism by which they correct the “genome errors” (J Biol Chem. 1989 264(31):18679-86 - Cell. 60(2):189-98 -  J Biol Chem. 1992 267(10):6782-8 -  EMBO J. 1995 14(1):178-87.)

• Polyphosphate metabolism in trypanosomatids and used of bisphonates as pharmacological compounds

Norbert Bakalara reported the identification and the functional characterization in trypanosomatid of a soluble pyrophosphatase (VSP1) that localizes in acidocalcisomes, a specific vesicular acidic compartment of trypanosomatid which plays a key role in polyphosphate metabolism. He demonstrated that VSP1 was essential for trypanosomatids in vivo development making the VSP1 enzyme as an attractive drug target against trypanosomatids. Bisphophonate were designed to inhibit VSP1 and the most active compound was shown  in vivo to provide a 40% protection from death with no apparent side effects. (J Biol Chem. 2000 275(12):8863-71 - J Biol Chem. 2002 277(40):37369-76 - J Biol Chem. 2004 279(5):3420-5 - J Med Chem. 2005 48(19):6128-39).

• Phostine: a new family of compounds opening therapeutic perspectives for glioblastoma
  
• 7-beta hydroxycholesterol in glioblastoma cells proliferation and death. 

 Phostines are glycomimetics which bear a phosphinolactone ring and specifically designed as bioisostere of sugar. We showed that phostines inhibit glioblastoma “stem cells” N-glycosyaltion resulting in a cytotoxic effect and inhibition of neurosphere formation (J Med Chem. 2012 55(5):2196-211).

Oxysterols possess anti-proliferative properties that may be used with much effect in the treatment of cancer. We have demonstrated for the first time that 7 beta-hydroxycholesterol provokes both metabolic stress, as witnessed by AMPK activation, and changes in lipid raft composition in C6 glioblastoma cells. (Biochem Pharmacol. 2013 86(1):161-7 - Biochem Pharmacol. 2013 86(1):154-60 - Biochem Pharmacol. 2012 (1):37-46)

• Industrial and Clinical transfer

We are currently creating a star-up called PHOST’IN in order to promote the clinical transfert of the phostine lead against glioma.

2 patents

• New phosphorus containing heterocyclic compounds, sugar analogs, and compositions having anticancer activity containing the same (EP 2170912 B1 granted on april 6^th 2011 - US 8383609 B2 granted on february   26^th 2013
• 2^nd patent Fr 13 51654 filed on february 25^th 2013

• Fundings

ANR PCV "G2O"

ANR Emergence Bio "IDPHOST"

INSERM/INCA transversal programme "GLIOMATRACK"

INCA "Phostine and glioma"

Languedoc Roussilon Incubation (LRI) "Phost'in"

Société d’accélération du transfert de technologies (SATT-AxLR)

INSERM - CNRS - ENSCM - UM1