New concept of resensitization to chemotherapy by activating the nucléoside kinase dCK by masitinib, a protein tyrosine kinase inhibitor.

La résistance à la chimiothérapie constitue un frein majeur à son efficacité. Notre équipe a récemment pu montrer que le masitinib, un nouvel inhibiteur de protéines tyrosine kinases, possède une activité de resensibilisation des cellules tumorales résistantes à la chimiothérapie lorsqu'il est combiné à certaines chimio-drogues. L'objectif des travaux de cette thèse est de déterminer les voies de signalisation, modulées par l'action du masitinib, qui sont impliquées dans la resensibilisation aux chimiothérapies et amélioration de l'activité anti-tumorale.Dans la première partie de la thèse, nous avons pu identifier la nucléoside kinase dCK (désoxycytidine kinase), protéine activatrice d'un grand nombre de chimiothérapies, comme nouvelle cible du masitinib. Cette première étude nous a permis de mettre en évidence un nouveau concept thérapeutique: le masitinib, un composé chimique de type inhibiteur de protéines tyrosine kinases, peut jouer en même temps le rôle d'activateur de nucléoside kinase.Nous avons pu mettre en évidence dans la deuxième partie de la thèse que le traitement combiné entre l'épi-drogue décitabine et le masitinib peut être plus efficace pour la réexpression de certains gènes non ou peu induits par la décitabine seule.En conclusion, ces travaux nous ont permis de mettre en évidence l'interaction entre un inhibiteur de protéine tyrosine kinases et une nucléoside kinase, dans un concept d'activation enzymatique qui pourra certainement servir de base pour l'élaboration de nouvelles petites molécules chimiques spécifiques de l'activation de dCK ou d'autres nucléosides kinases nécessaires à l'activation des drogues de chimiothérapie.Resistance to chemotherapy is considered as one of the major blockers of its efficacy. Recently, our team demonstrated that masitinib, a new tyrosine kinases inhibitor, possesse a resensitization activity of cell lines resistant to chemotherapy when associated with chemodrugs.The aim of this work is to determine signaling pathways, modulated by masitinib action, that could explain the resensitization to chemotherapy and improvement of anti-tumoral activity.In the first part of this work, we identified the nucleoside kinase dCK (deoxycytidine kinase), a chemotherapy activating protein, as a new target of masitinib. In summary, this first part of the work allowed us to describe a new and never described concept: masitinib, a small molecule belonging to tyrosine kinases group, can also play a role as nucleoside kinase activator.We were able to demonstrate through the second part of the work that the combined treatment of the epidrug decitabine and masitinib can be more effective than decitabine treatment for the re-expression of some genes non or weakly induced by decitabine when used alone.In conclusion, These data allowed us to introduce an interaction between a tyrosine kinases inhibitor and a nucleoside kinase, as an enzymatic activation new concept. This could be used as a base for the design of new small chemical molecules specific for dCK or other nucleoside kinases essential for the activation of chemodrugs. This concept will obviously help to imagine and evaluate more potential therapeutic combinations of chemodrugs and small chemical molecules to overcome the resistance to chemotherapy dependent on nucleoside kinases

Preoperative language rehabilitation in drug-resistant temporal lobe epilepsy (PReLang): Protocol for a randomized controlled study

Introduction: Drug-resistant epileptic patients who undergo a left anterior temporal lobectomy often experience increased naming difficulties following surgery (41% of cases). Prehabilitation, i.e., rehabilitation before surgery, could induce protective brain plasticity, likely to increase cognitive reserve, particularly for patients with high risk of postoperative cognitive decline. The efficiency of language prehabilitation on postsurgical outcomes has never been thoroughly tested. The present study is the first one testing a possible protective effect of preoperative language rehabilitation in temporal lobe epilepsy surgery.Methods and analysis: The planned study (PReLang – REPREO) is a two-year large-scale randomized controlled trial of the pre-surgical management of language processing in the context of left temporal lobe epilepsy surgery. A total of 214 subjects waiting for anterior temporal lobectomy will be randomized and assigned either to the control group —who will benefit from standard of care — or to the experimental group — who will benefit from a language prehabilitation designed to protect against post-operative language decline. Both groups will undergo the same language assessments and questionnaires before surgery, seven days after surgery, and six months far from surgery

BDNF as potential biomarker of epilepsy severity and psychiatric comorbidity: pitfalls in the clinical population

International audienceBackgroundSeveral studies implicate brain-derived neurotrophic factor (BDNF) in the pathophysiology of epilepsy. In particular, preclinical data suggest that lower serum BDNF is a biomarker of epilepsy severity and psychiatric comorbidities. We tested this prediction in clinical epilepsy cohorts.MethodsPatients with epilepsy were recruited from 4 epilepsy centers in France and serum BDNF was quantified. Clinical characteristics including epilepsy duration, classification, localization, etiology, seizure frequency and drug resistance were documented. Presence of individual anti-seizure medications (ASM) was noted. Screening for depression and anxiety symptoms was carried out in all patients using the NDDI-E and the GAD-7 scales. In patients with positive screening for anxiety and/or depression, detailed psychiatric testing was performed including the Mini International Neuropsychiatric Interview (MINI), STAI-Y, Holmes Rahe Stressful Events Scale and Beck Depression Interview. Descriptive analysis was applied. Spearman’s test and Pearson’s co-efficient were used to assess the association between BDNF level and continuous variables. For discrete variables, comparison of means (Student’s t-test, Mann-Whitney u-test) was used to compare mean BDNF serum level between groups. Multivariate analysis was performed using a regression model.ResultsNo significant correlation was found between serum BDNF level and clinical features of epilepsy or measures of depression. The main group-level finding was that presence of any ASM at was associated with increased BDNF; this effect was particularly significant for valproate and perampanel.ConclusionPresence of ASM affects serum BDNF levels in patients with epilepsy. Future studies exploring BDNF as a possible biomarker of epilepsy severity and/or psychiatric comorbidity must control for ASM effects

Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology

Masitinib is a protein kinase inhibitor that sensitises refractory pancreatic adenocarcinoma cells to treatment with the nucleoside analog gemcitabine. Here the authors show that Masitinib activates deoxycytidine kinase to enhance phosphorylation of nucleoside analogue pro-drugs, increasing their potency