Patient-derived 3D sarcoma model - robust system for sarcoma research and personalized therapy selection

Abstract

Recent progress in 3D cell culture models largely advanced the field of personalized medicine in carcinomas. Unfortunately, the situation is different for the sarcomas: the clinical treatment of sarcoma patients has not significantly improved in the last decade. Such a discrepancy stems from the high degree of heterogeneity of sarcomas and the limited knowledge of the molecular drivers of the tumorigenesis and progression. Our group developed the patient-derived 3D (PD3D) sarcoma model as a tool for a systematic sarcoma research and personalized therapy selection. In short, fresh surgical specimens undergo mechanical and chemical dissociation, cell aggregates are embedded in matrix-like scaffolds and allowed to form colonies. After harvesting the cells undergo pathology evaluation to confirm origin and diagnosis. Standard-of-care compounds as wells as experimental drugs are used for drug sensitivity testing after transferring cells semi-automatically to 384-well plates. Here we report that our PD3D sarcoma model is suitable for the screening of multiple chemotherapeutic compounds in a wide range of sarcoma subtypes. So far, we obtained 57 sarcoma samples. As expected, the most common diagnoses within our cohort are liposarcoma (31.58%) and Undifferentiated pleomorphic sarcoma (UPS) (15.79%). As a proof of the concept, we performed 10 drug-screening experiments with different sarcoma subtypes utilizing first and second line treatment chemotherapeutic compounds. The mean time between obtaining of the sample and drug-screening result was 69 days. Epirubicin, doxorubicin and actinomycin D showed robust activity throughout the whole spectrum of sarcomas tested. Ifosfamide did not show any significant effect, probably due to the requirement for its activation by liver enzymes. Interestingly, trabectedin demonstrated the best effect through the whole samples tested with the IC50s at list 3 orders of magnitude lower than the maximally reachable plasma concentration. Trabectedin is currently only approved as a second line treatment for liposarcoma and leiomyosarcoma by the FDA. Our results indicate that it could be beneficial for patients with other sarcoma subtypes. Even with the limited number of samples we accumulated a variety of different histopathological sarcoma subtypes in our collection. We hope that further development of our collection will allow us to cover the whole spectrum of sarcomas, generating much needed tool for investigating soft-tissue tumors, and allowing for successful development of a targeted therapeutic approach. Overall, our results indicate, that sarcoma PD3D cultures are a viable option for personalized medicine approach, previously unavailable for sarcoma patients.