Descrizione del progetto
Meccanismi genetici nella patobiologia dei sarcomi pediatrici
L’attuale trattamento dei sarcomi, compresi i sarcomi pediatrici, dispone di opzioni terapeutiche limitate rispetto ad altri tumori. Pertanto, la generazione di modelli in vitro e in vivo per la ricerca sul sarcoma è urgentemente necessaria per una migliore comprensione della patobiologia di questi tumori. Molti tipi di sarcomi pediatrici dei tessuti molli possiedono un meccanismo genetico sottostante simile, in cui le traslocazioni cromosomiche generano oncoproteine di fusione che fungono da fattori guida della malattia. Il progetto PedSarc, finanziato dall’UE, mira a sfruttare queste specifiche genetiche dei sarcomi pediatrici per sviluppare terapie efficaci e specifiche. I ricercatori impiegheranno le tecnologie CRISPR/Cas9 e RNAi per identificare i principali attori della deregolazione epigenetica nei sarcomi pediatrici e generare nuovi modelli murini per aiutare la traduzione clinica e lo sviluppo di nuovi bersagli terapeutici per le malattie.
Obiettivo
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.
Campo scientifico
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Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
69120 Heidelberg
Germania