Project description
Genetic mechanisms in pathobiology of paediatric sarcomas
Current treatment of sarcomas, including paediatric sarcomas, has limited therapeutic options compared to other cancers. Therefore, generation of in vitro and in vivo models for sarcoma research is urgently needed for better understanding of the pathobiology of these tumours. Many types of soft tissue paediatric sarcomas have a similar underlying genetic mechanism, where chromosomal translocations generate fusion oncoproteins that serve as drivers of the disease. The EU-funded PedSarc project aims to take advantage of these genetic specifics of paediatric sarcomas to develop effective and specific therapies. Researchers will employ CRISPR/Cas9 and RNAi technologies to identify key players in epigenetic deregulation in paediatric sarcomas, and generate new mouse models to assist clinical translation and development of the new therapeutic targets for the diseases.
Objective
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.
Fields of science
Keywords
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
69120 Heidelberg
Germany