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Heterogeneity, Evolution and Resistance of Fusion-driven Sarcomas in Adolescents and Young Adults (BMBF)

Tumors evolve through genetic and non-genetic changes, leading to intra-tumoral heterogeneity (ITH), a key factor in relapse and therapy resistance. Our focus is on bone and soft-tissue sarcomas caused by chimeric fusion genes. These serve as model diseases to investigate ITH in cancers with defined genetic drivers, translating findings into innovative treatment strategies against diverse and evolving tumors. Challenges include limited effective therapies, stagnant outcomes, and early onset, emphasizing the urgency to improve sarcoma patient outcomes. Fusion-driven sarcomas (FDS) offer a unique opportunity due to their entity-defining fusion genes, aiding the study of subclones and plasticity. FDS also exhibit low genetic complexity, facilitating the identification of ITH-promoting factors and responses to therapy. Leveraging the expertise of HEROES-AYA, an international precision oncology network, we aim to study FDS at diagnosis and during therapy resistance through cutting-edge analyses at single-cell and spatial levels. In vitro and in vivo validations of vulnerabilities will inform the development of clinical trials spanning age groups, ushering in a new era of precision oncology in Germany. The group substantially contributes to the data science aspects of this project.

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