The role of novel antiangiogenic and other targeted treatments in soft tissue sarcoma

STS represents a rare and highly diverse group of mesenchymal neoplasms, consisting of more than 50 subtypes. One of the most common STS histotypes is liposarcoma, originating from adipose tissue. Surgery is the primary treatment for resectable liposarcoma. Patients with unresectable or advanced disease require systemic treatment, but established drugs provide only marginal palliative effects, emphasizing the urgent need of novel therapeutic options. Recent studies revealed that the angiogenesis and PI3K signalling pathways are implicated in the pathogenesis of liposarcoma, suggesting thatinhibition of these targets could be considered as promising therapeutic strategy. Generally, the development of novel therapies for liposarcoma is hindered by the low incidence of sarcoma in general and a relative lack of reliable preclinical models. In the present study, tumours specimen from 68 STS patients were transplanted in mice, resulting in 12 established xenografts plus a number of further models in early stages of passaging. All established models are well characterized by histopathological and molecular means, and nicely match the morphology and genotype of the original tumour samples. Subsequently the targeted compounds CABO, PAZ, and GDC were tested in DDLPS xenograft models in vivo and were administrated either as single agent, as combinations or in combination with conventional chemotherapy. CABO, which mainly targets VEGFR and MET, was found to capable of delaying tumour growth by suppressing cell proliferation, enhancing apoptosis and inhibiting tumour angiogenesis. The drug should be studied in clinical liposarcoma studies.PAZ, which shows antiangiogenic and antitumour effects in various cancer types and is approved for treatment of advanced non-adipocytic STS, inhibited cell proliferation and reduced vascular density in all tested DDLPS models. While the combined use of PAZ and cytotoxic chemotherapy was not foundto be promising strategy in liposarcoma, the combination with other targeted agents holds some promise.GDC, a specific PI3K inhibitor, was found to suppress the activation of PI3K-AKT pathway in vitro and in vivo, and induced tumour growth delay in all tested DDLPS, through antiproliferative and proapoptotic effects. In combination with the angiogenesis inhibitor PAZ, synergy was observed in selected models. Clinical trials exploring such combination in DDLPS are warranted.status: publishe