Abstract 1660P
Background
Soft tissue sarcomas (STS) are a rare group of mesenchymal tumors accounting 1% of all adult cancers. The most common STS in adult are liposarcoma, leiomyosarcoma and undifferentiated pleomorphic sarcoma. Although they exhibit different biological and clinical behavior as chemotherapy sensitivity, the current fist-line treatment for advanced or metastatic STS is based on anthracyclines. Second-line therapy may include trabectedin, eribulin, ifosfamide, gemcitabine and dacarbazine with no optimized standard sequential therapy. In particular, trabectedin activity as its mechanism of action is not completely decoded.
Methods
The study enrolled ten STS patients. Combining our STS translational model based on 3D patient-derived primary cultures system and zebrafish we performed genomic-, pharmacological (testing ifosfamide, epirubicin, ifosfamide and epirubicin, doxorubicin, trabectedin, eribulin, dacarbazine and lenvatinib) proteomic- and in silico analysis.
Results
The results confirmed the ability of our model in recapitulating morphological features and genomic landscape of STS lesions. UPS chemobiogram profiling revealed the sensitivity to chemotherapy with the highest activity exhibited by anthracyclines and trabectedin. Contrarily to all tested drugs, trabectedin exhibited a higher activity in 3D suggesting an extracellular matrix (ECM) involvement in its mechanism of action confirmed also by Casp-3 upregulation as the ECM-related gene timp1. The results were corroborated in a UPS zebrafish xenograft model which showed a more susceptibility to trabectedin in 3D. Finally, the results were validated in a STS case series in which trabectedin exhibited a higher activity in 3D among all treatment groups. In silico analysis confirmed the prognostic role of timp1, mmp2 and col1a1 in STS disease.
Conclusions
The results confirmed the activity of trabectedin in UPS and L-sarcomas. Moreover the data suggest the ECM involvement in the execution of the cytotoxic effect mediated by the drug and could open the door for further researches aimed to focus on which patients could benefit from trabectedin and which not.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Toni Ibrahim.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.