Targeting soft tissue sarcoma with smart molecules - exploring cytotoxic prodrugs and target-specific inhibitors in patient-derived xenografts

Soft tissue sarcomas (STS) are malignant tumours that originate in soft tissues, which connect, support and surround body structures and include for example muscle and fat. STS are a group of very diverse and rare tumours. Most STS have an aggressive behaviour, especially if diagnosed when the disease is in a more advanced stage. The current systemic standard therapies have very unsatisfactory effects in most subtypes of STS, with 1-year and 5-year survival rates of 75.1 and 50.4%, respectively. Furthermore, all available treatments have some degree of toxicity which can be cumulative and irreversible.The aim of this PhD project is to evaluate the use of innovative drugs in vivo, using established and new STS mouse models. These models are created using patient-derived tumour tissue. One attractive strategy is the development of prodrugs, which under ideal circumstances are inactive in normal cells but are converted to the active drug by drug-activating enzymes only present in cancer cells or tumour microenvironment. This should minimize toxicity for normal cells and could increase the antitumour efficacy. Another approach is the use of specific inhibitors of relevant oncogenic intracellular signalling pathways. Hopefully, the most promising results will translate into clinical research, where the identified drug candidate(s) will be tested in patients with STS.