Description du projet
Les mécanismes génétiques dans la pathobiologie des sarcomes pédiatriques
Le traitement actuel des sarcomes, y compris des sarcomes pédiatriques, dispose d’options thérapeutiques réduites par rapport à d’autres cancers. Par conséquent, la génération de modèles in vivo et in vitro pour la recherche sur le sarcome est nécessaire de toute urgence afin de mieux comprendre la pathobiologie de ces tumeurs. De nombreux types de sarcomes pédiatriques des tissus mous ont un mécanisme génétique sous-jacent semblable, où les translocations chromosomiques génèrent des oncoprotéines de fusion qui provoquent la maladie. Le projet PedSarc, financé par l’UE, entend tirer profit de ces particularités génétiques des sarcomes pédiatriques pour développer des traitements spécifiques et efficaces. Les chercheurs utiliseront les technologies CRISPR/Cas9 et ARNi pour identifier les principaux acteurs de la dérégulation épigénétique des sarcomes pédiatriques, et pour obtenir de nouveaux modèles murins afin de permettre la traduction et le développement cliniques de nouvelles cibles thérapeutiques destinées à ces maladies.
Objectif
Sarcomas are an extremely heterogeneous group of mesenchymal tumors that arise in a multitude of tissues from many different cell types. Several genetic events have been identified in different sarcoma sub-types, but very few models were developed to study their role in tumorigenesis aiming at exploiting them as therapeutic vulnerabilities. As a result, the treatment of sarcoma has extremely limited advancement in therapeutic options compared to other cancers. Therefore, the generation of faithful in vitro and in vivo models for sarcoma research is urgently needed to provide insights into the pathobiology of these tumors and discover novel vulnerabilities in these lethal but yet understudied disease. Many types of soft tissue sarcomas arising in children and young adults have a unifying underlying genetic mechanism, where chromosomal translocations generate fusion oncoproteins that serve as drivers of the disease. Exploiting this genetic simplicity provides an exceptional opportunity to develop effective and specific therapies. My past research has applied cutting edge technology to define epigenetic vulnerabilities associated with the SS18-SSX gene fusion, the defining event in synovial sarcoma (one subgroup of pediatric sarcomas), and to study its chromatin occupancy genome-wide. In this proposal my team will combine a toolbox consisting of CRISPR/Cas9, RNAi technology and expertise in mouse models to systematically elucidate key genetic and epigenetic mechanisms in the pathobiology of pediatric sarcomas. This work will help to understand key players in epigenetic deregulation in pediatric sarcomas, generate new sarcoma models to assist clinical translation, and identify new therapeutic targets for these deadly diseases.
Champ scientifique
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ERC-STG - Starting GrantInstitution d’accueil
69120 Heidelberg
Allemagne