Function and Inhibition of Therapeutic Targets in

Il y a 2 mois

Marseille, France Centre de Recherche en cancérologie de Marseille (CRCM) Temps plein

**Function and inhibition of therapeutic targets in leukemia**:

- Réf **ABG-125962**
- Sujet de Thèse- 24/09/2024- Autre financement public- Centre de Recherche en cancérologie de Marseille (CRCM)- Lieu de travail- Marseille - Provence-Alpes-Côte d'Azur - France- Intitulé du sujet- Function and inhibition of therapeutic targets in leukemia- Champs scientifiques- Biologie
- Biochimie
- Santé, médecine humaine, vétérinaire
- Mots clés- leucémie, cible thérapeutique, protéine kinase, inhibiteurs**Description du sujet**:

- Cyclin-dependent kinase 6 (CDK6) is a crucial regulator of highly aggressive acute myeloid leukemia (AML) and a recognized therapeutic target. Understanding the mechanisms initiated by CDK6 inhibition is essential to reveal therapeutic windows enabling novel combinatorial treatment strategies. We propose to clarify the mechanism by which CDK6 regulates vesicle biogenesis and function and in turn the microenvironment. We will investigate whether the combination of CDK6 inhibitors with drugs targeting vesicle regulation can benefit AML patients.- We will take advantage of existing CDK4/6 kinase inhibitors and genetically-modified cell models expressing a CDK6 mutant. We will define how CDK6 regulates vesicle biogenesis and function via transcriptional regulation and protein interaction by integrating ChIP-Seq, transcriptomic and phospho-proteomic data. We will get deeper insights if CDK6 inhibition changes the AML-EV cargo and if these changes effect leukemic niche cells, by establishing a 3D model with stromal, endothelial and healthy hematopoietic cells with AML-EVs. In this model, cells will be characterized through phenotypical and functional assays and the transcriptomic pattern will be determined by RNA-Seq. A combinatorial drug screen with CDK6 inhibitors and small molecules targeting vesicle biogenesis and function will be implemented to investigate novel therapeutic strategies.**Prise de fonction**:

- 03/03/2025**Nature du financement**:

- Autre financement public**Précisions sur le financement**:

- ANR 3 ans**Présentation établissement et labo d'accueil**:

- Centre de Recherche en cancérologie de Marseille (CRCM)Le Centre de Recherche en Cancérologie de Marseille (CRCM) est affilié à l’Inserm (UMR1068), au CNRS (UMR7258), à l’Université Aix-Marseille (UM105) et au Centre de Lutte Contre le Cancer de la région PACA, l’Institut Paoli-Calmettes (IPC).

Il comprend près de 450 personnes dans 21 équipes et 18 plateformes/plateaux technologiques coordonnés sous forme d’un Core Tech. C’est un centre avec plus de 25 nationalités représentées, collaborant avec les plus grands instituts nationaux et internationaux et membre de multiples réseaux d’excellence de recherche sur le cancer.

La recherche au CRCM aborde les aspects fondamentaux de la recherche en cancérologie, allant de l’initiation au développement du cancer jusqu’à sa dissémination sous forme plus agressive (métastatique) en identifiant les altérations moléculaires, les mécanismes d’instabilité du génome et de sa réparation et en étudiant leurs conséquences fonctionnelles dans des contextes in vitro et in vivo. La contribution du microenvironnement tumoral et du système immunitaire est un autre domaine de recherche important du CRCM. Cette recherche interdisciplinaire est effectuée aux niveaux moléculaire, cellulaire et physiopathologique, à l’aide de modèles cellulaires simples ou complexes (organoïdes) ou récapitulant chez l’animal les étapes du processus tumoral. Ces approches multi-échelles permettent d’identifier de nouvelles cibles thérapeutiques et visent à développer des approches innovantes ciblant les altérations de la cellule cancéreuse ou de son environnement dans le but de progresser vers de nouveaux traitements.

**Site web**:
**Etablissement délivrant le doctorat**:

- Aix-Marseille UniversitéMotivé, curieux, sérieux, ponctuel, travailleur.

Parcours universitaire très bon à excellent.

Master 2 réalisé en 2024 ou 2023.- 31/10/2024

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