Descripción del proyecto
Mecanismos genéticos en la patobiología de los sarcomas pediátricos
El tratamiento actual de los sarcomas, incluidos los sarcomas pediátricos, presenta opciones terapéuticas limitadas en comparación con otros tumores. Por lo tanto, se requiere con urgencia el desarrollo de modelos «in vitro» e «in vivo» para la investigación de los sarcomas a fin de comprender mejor la patobiología de estos tumores. Muchos tipos de sarcomas pediátricos de tejidos blandos presentan un mecanismo genético subyacente similar, en el que las translocaciones cromosómicas generan oncoproteínas de fusión que sirven como impulsores de la enfermedad. El objetivo del proyecto financiado con fondos europeos PedSarc es aprovechar estas especificidades genéticas de los sarcomas pediátricos para desarrollar terapias eficaces y específicas. Los investigadores emplearán las tecnologías CRISPR/Cas9 y de ARN de interferencia para identificar los principales agentes relacionados con la desregulación epigenética en los sarcomas pediátricos y crearán nuevos modelos murinos para ayudar a la traslación clínica y al desarrollo de nuevas dianas terapéuticas para las enfermedades.
Objetivo
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.
Ámbito científico
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ERC-STG - Starting GrantInstitución de acogida
69120 Heidelberg
Alemania