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Molecule banks help discover medicinal drugs against leukaemia

Why not imag­ine ran­dom­ly test screen­ing mil­lions of mol­e­cules to seek out the rare for­mu­la that could inter­act effi­cient­ly with a pro­tein tar­get­ed in leukaemia patients? This is the orig­i­nal approach adopt­ed by Bérangère Bihan-Avalle and her research team that led to the lodg­ing of a patent claim for two mol­e­cules that poten­tial­ly might prove attrac­tive in the fight against chron­ic leukaemia. 

In the field of med­ical research, chance occa­sion­al­ly plays a role. If the staphy­lo­coc­ci bac­te­r­i­al cul­ture stud­ied by Alexan­der Flem­ing in 1928 had not been con­t­a­m­i­nat­ed by a wind-borne fun­gus peni­cil­li­um nota­tum [his lab. neigh­bour and assis­tant had inad­ver­tent­ly left the win­dow open dur­ing the night], he prob­a­bly would not have dis­cov­ered that very impor­tant antibi­ot­ic penicillin. 

But serendip­i­ty is not the leit­mo­tiv of the approach devel­oped by Pro­fes­sor Bérangère Bihan-Avalle, in charge of the theme Mol­e­c­u­lar Diver­si­ty and Bio­catal­y­sis, in her efforts to dis­cov­er new mol­e­cules to fight leukaemia. Nonethe­less, there is a ran­dom fac­tor in her work. 

“Our team is spe­cial­ized in using mol­e­cule banks with mil­lions or even bil­lions of sam­ples, so that we can iden­ti­fy those that poten­tial­ly could inter­act with a pre­de­fined tar­get”, explains the research sci­en­tist — who indeed recent­ly was suc­cess­ful in iden­ti­fy­ing two mol­e­cules that could be uses in cas­es of chron­ic myeloid leukaemia. 

A proliferation of undifferentiated cells

Leukaemia are can­cers of white blood cells that can be dif­fer­ent depend­ing on the type of cell affect­ed. Among these there are the myeloid cells or the lym­pho­cyte cells which play an impor­tant role in our immu­ni­ty sys­tem. These cell under­go genet­ic muta­tions or chro­mo­some translo­ca­tions (where DNA frag­ments shift from one chro­mo­some to anoth­er) and lead to an unusu­al­ly high pro­tein pres­ence (e.g., the STAT5** pro­tein) which is a fac­tor for genet­ic tran­scrip­tion and inter-cell sig­nalling systems. 

When con­stant­ly acti­vat­ed, this pro­tein is respon­si­ble for anar­chic cell pro­lif­er­a­tion which is the symp­tom of leukaemia. The cells total­ly invade the bone mar­row and then the patien­t’s blood stream.**signal trans­duc­er and acti­va­tor of transcription. 

Multiplying the number of potential molecules

In a part­ner­ship with the Oise Depart­ment Ligue con­tre le Can­cer (a char­i­ty fund) and with finan­cial sup­port from the Picardie Region­al author­i­ties, Bérangère Bihan-Avalle and her team use oligonu­cleotide (DNA frag­ments) banks seek­ing those that could have an effect on can­cer cells.In vit­ro, the sci­en­tists have test­ed mil­lions of “can­di­dates” to iso­late those that may inter­act with the famous STAT5 protein. 

“Our objec­tive is to screen syn­the­sized oligonu­cleotide banks ran­dom­ly with the hope that we shall find can­di­dates capa­ble of inhibit­ing or inac­ti­vat­ing the STAT5 pro­tein”, explains Bérangère Bihan-Avalle. Two mol­e­cules have indeed been iden­ti­fied in the process and are being test­ed cur­rent­ly to eval­u­ate their effects on pro­lif­er­a­tion of leukemia cells. 

Avoiding any preconceived ideas

“Our approach had the advan­tage of allow­ing us to begin work with­out any a pri­ori ideas about the mol­e­cules we were seek­ing”, under­scores Bérangère Bihan-Avalle who hopes to dis­cov­er some inno­v­a­tive med­i­c­i­nal sub­stances. The method is very dif­fer­ent from that used in the phar­ma­ceu­ti­cal sec­tor actors who gen­er­al­ly take their inspi­ra­tion from an already known mol­e­cule and derive a vari­ant that proves more effi­cient or bet­ter adapt­ed to the case, dis­or­der or illness. 

Using mol­e­cule banks enables you to dis­cov­er sub­stances that it would be dif­fi­cult to con­ceive via a ratio­nal approach. Today’s med­i­c­i­nal drugs used to fight leukaemia unfor­tu­nate­ly only have lim­it­ed effi­cien­cy. The cur­rent rate runs between 80% and 30% depend­ing on the type of leukaemia. There is no drug as yet that specif­i­cal­ly deals with the STAT5 protein. 

Taking action in the heart of the cells 

Two mol­e­cules are sub­ject to a patent claim pro­ce­dure at the moment, but the work con­tin­ues, notably to under­stand how these mol­e­cules can oper­ate inside the tar­get­ed cells. Using mol­e­cule banks enables you to dis­cov­er sub­stances that it would be dif­fi­cult to con­ceive via a ratio­nal approach. Today’s med­i­c­i­nal drugs used to fight leukaemia unfor­tu­nate­ly only have lim­it­ed effi­cien­cy. The cur­rent rate runs between 80% and 30% depend­ing on the type of leukaemia. There is no drug as yet that specif­i­cal­ly deals with the STAT5 pro­tein. Tak­ing action in the heart of the cells Two mol­e­cules are sub­ject to a patent claim pro­ce­dure at the moment, but the work con­tin­ues, notably to under­stand how these mol­e­cules can oper­ate inside the tar­get­ed cells. 

“One dif­fi­cul­ty resides in try­ing to ‘design’ an active mol­e­cule capa­ble of pen­e­trat­ing the cell mem­brane with­out alter­ing its action capac­i­ty on the pro­tein”, explains Bérangère Bihan-Avalle, who adds that this thrust of her research has only just begun. In the long run, it is envis­ages that the team will be able to test the mol­e­cules iden­ti­fied on human tumours trans­plant­ed to ani­mals, if and when part­ner­ships in this direc­tion have been agreed with the phar­ma­ceu­ti­cal lab­o­ra­to­ries inter­est­ed. For the moment, her research is enter­ing its pre­lim­i­nary phase but with the prospect of a devel­op­ment peri­od last­ing some ten years. 

“We need to take our time to char­ac­ter­ize the mol­e­cules we shall have iden­ti­fied and to pub­lish the research results before we set up any part­ner­ship with a pri­vate sec­tor lab­o­ra­to­ry”, con­cludes Bérangère Bihan-Avalle, whose opin­ion it is that indus­tri­al pres­sure could prove coun­ter­pro­duc­tive. Research on these oligonu­cleotides poten­tial­ly capa­ble of act­ing on tar­get­ed pro­teins is too recent and, as such, has made the phar­ma­ceu­ti­cal lab­o­ra­to­ries rel­a­tive­ly ret­i­cent, for the time being. To date, only one mol­e­cule of this cat­e­go­ry has been made into a med­ical drug. 

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