Biologie van synoviaal sarcoom en het onderzoek naar nieuwe therapeutische mogelijkheden voor deze zeldzame ziekte.

Soft tissue sarcoma represents a very heterogeneous group of tumors of mesenchymal origin and accounts for about 1% of all adult cancers. Despite the heterogeneity in soft tissue sarcomas, the standard treatment options are very uniform and have limited efficacy. There is a need for a more subtype-specific approach to develop more effective treatment options. In this PhD project, we focused specifically on one of the more common subtypes of soft tissue sarcoma: synovial sarcoma. It is characterized by a translocation between the SYT gene on the 18th chromosome and one of the SSX genes on the X chromosome, resulting in the pathognomonic SS18::SSX fusion. For localized synovial sarcoma, treatment typically consists of surgery, combined with chemo-or radiotherapy in some cases. Patients with metastatic synovial sarcoma are usually treated with systemic chemotherapy and although synovial sarcoma can respond to systemic therapy, the outcome of patients with metastatic disease remains very poor. The first aim of this research project was to explore the clinical disease course of 134 adult patients diagnosed with synovial sarcoma and treated at the University Hospitals Leuven, Belgium, between 1987 and 2018. This retrospective series confirmed that most patients were diagnosed with localized disease, but although they received treatment with curative intent at a sarcoma reference center, almost half of these patients developed metastases. Treatment options in advanced and metastatic setting resulted in poor outcomes. This clearly emphasized the need to develop better treatment strategies for these patients. The development of T cell receptor therapies will hopefully improve the outcome of patients with SynSa in the future. A better understanding of the expression of this treatment's targets is needed to understand which patients might be eligible for this therapy and which clinicopathological factors might influence the expression. We provided one of the first real-world data on this topic. Secondly, also the expression of other potentially actionable targets such as bromodomain-containing protein 9, chemokine receptor 4 and key regulators of the Hippo pathway: yes associated protein 1 and transcriptional co-activator with PDZ-binding motif were investigated. All evaluated markers were expressed in a clinically meaningful proportion of cases represented in our samples, supporting the relevance of ongoing preclinical and clinic research with novel agents directed against these targets. The third aim of this research project focused on the expansion of the currently available preclinical models of synovial sarcoma and the creation of novel preclinical models, such as tumoroids. Several patient-derived preclinical models of synovial sarcoma were created within this project: primary cell cultures, tumoroids and patient-derived xenografts. These models are well characterized, ensuring the key characteristics of the original patient's tumor are present and corresponding clinicopathological information is available. Most of these models can be exchanged with collaborators and used for subsequent experiments as highlighted in one of the subchapters. Given the rarity of this disease, these models are very valuable. The creation of tumoroids from synovial sarcoma only had limited success and required an extensive optimization of the culture conditions. Based on this experience, an active working group connecting researchers working with tumoroid models of sarcoma was founded and recommendations to guide others working on this topic were written. In conclusion, this thesis offered a deeper insight into the clinical presentation of patients with synovial sarcoma. We explored the expression of several novel actionable targets, enhancing our understanding of potential therapeutic opportunities. Secondly, preclinical models were developed and characterized to evaluate novel treatment approaches. Lastly, this work established strong foundations for ongoing and future collaborations.