Multi-level characterization of bone and soft-tissue sarcoma for precision sarcoma medicine

• Applicant: Dr. Priya Chudasama, Ph.D.
• Subject Area: Hematology, Oncology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 415971346

Sarcomas are a large and heterogeneous group of aggressive tumors with significant genetic and histologic diversity, variable clinical course and very few treatment options. Numerous clinical trials have shown that in advanced-stage sarcoma, conventional chemotherapy may provide symptom palliation and delay disease progression but does not prolong survival, which typically ranges from 11 to 15 months after the development of distant metastases. Thus, there is an urgent need to develop more effective and well-tolerated therapies. The proposed research program aims to address this challenge by systematic investigation of the genomic, epigenomic, transcriptomic and immunologic landscapes of a large cohort of prospectively collected and clinically annotated primary human sarcoma specimens employing state-of-the-art technologies, followed by investigation into the functional and mechanistic consequences of selected alterations. Potentially "actionable" targets will be taken forward to investigator-initiated clinical trials of biology-guided sarcoma treatments. Preliminary work identified several distinctive features, including a high frequency of alternative telomere lengthening in leiomyosarcoma as well as epigenetic deregulation of the FGFR1 receptor tyrosine kinase and the presence of immune cell infiltrates and expression of targets for immunotherapy in multiple sarcoma subtypes. To investigate these findings further, I will pursue the following objectives:1. Targeting perturbed telomere maintenance mechanisms in sarcomas with complex genetics2. Integrative analysis of deregulated epigenetic mechanisms in sarcoma3. Inquiry of the immune landscape of sarcomas to identify entry points for individualized immunotherapeutic approachesThe proposed work plan will improve the understanding of sarcomagenesis and identify targets for biological stratification and molecular mechanism-guided therapeutic intervention.

• DFG Programme: Independent Junior Research Groups