Emmy Noether Junior Research Group Precision Sarcoma Research

Sarcomas are mesenchymal malignancies of the connective tissues, which include fat, blood vessels, nerves, bone, muscles, deep skin tissues and cartilage. Sarcomas are mainly divided into two types, bone sarcoma and soft-tissue sarcoma. Sarcomas display remarkable genetic and histologic diversity, as reflected by more than 70 subtypes according to the World Health Organization Classification, which in turn poses significant diagnostic and therapeutic difficulties. 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. Despite these clinical challenges, sarcomas remain grossly underresearched. In particular, “actionable” lesions that allow prediction of response to conventional or targeted anti-cancer drugs and/or represent direct targets for therapeutic intervention are lacking in the majority of cases due to incomplete understanding of the events that drive sarcoma development.

The Precision Sarcoma Research group funded by the Emmy Noether Program of the German Research Foundation (DFG) has been established with the aim to better understand the molecular alterations underlying tumor development and to identify novel targets for precision cancer therapy. This is achieved 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 functional and mechanistic investigations of selected aberrations using suitable model systems and genome-editing methods (RNA interference, CRISPR/Cas9). Within the NCT Molecular Diagnostics Program, in particular the NCT/German Cancer Consortium (DKTK) MASTER (Molecularly Aided Stratification for Tumor Eradication) registry trial, more than 700 patient tumors encompassing about 55 sarcoma sub-entities contributed by multiple DKTK centers have been processed by next-generation sequencing technologies, allowing for pan-sarcoma and subtype-specific analyses, representing a unique resource in terms of number of tumors and diversity of subtypes to perform multi-level characterization of these tumors. Preclinical investigation of genetic lesions of interest is also enabled by a panel of sarcoma cell lines and organoids representing 11 sub-entities, a resource that is continuously expanded using freshly acquired tumor material.

Our previous work identified several distinctive features of sarcomas (see publications). We are currently pursuing the following objectives:

• Investigation of perturbed telomere maintenance mechanisms in sarcomas
• Integrative analysis of deregulated epigenetic mechanisms in sarcomas
• Targeting sarcoma drivers using drug-induced protein degradation
• Inquiry of the immune landscape of sarcomas to identify entry points for individualized immunotherapeutic approaches

These studies will improve the understanding of sarcomagenesis and identify targets for biological stratification and molecular mechanism-guided therapeutic intervention.