Antitumor activity of novel transcriptional inhibitors ecubectedin and PM54 in soft tissue sarcoma patient-derived xenografts

Abstract

Trabectedin, prototype of the ecteinascidin class of drugs, is a known second or later line therapeutic option for advanced soft tissue sarcoma (STS). We evaluated the antitumor activity of two novel synthetic trabectedin derivatives, ecubectedin and PM54, in selected patient-derived xenograft (PDX) STS models. In total 364 NMRInu/nu mice were transplanted bilaterally with two leiomyosarcoma (LMS), two dedifferentiated liposarcoma (DDLPS), one synovial sarcoma (SynSa) and one CIC-rearranged sarcoma (CRS) PDX models. Mice were randomized to six groups and treated via tail vein injection with 1) vehicle, 2) doxorubicin, 3) trabectedin, 4) lurbinectedin, 5) ecubectedin, or 6) PM54. Treatment was given on days 1, 8 and 15, and mice were sacrificed on day 16. The SynSa experiment included extra mice to investigate post-treatment xenograft evolution. Antitumor activity was assessed by tumor volume measurement, histopathologic and immunohistochemical analysis. In all LMS and DDLPS models, ecubectedin and PM54 led to tumor growth delay compared to trabectedin. Histopathological evaluation of treated tumors showed moderately increased antitumor activity of novel ecteinascidins compared to trabectedin. The CRS showed tumor shrinkage in response to ecubectedin (63% regression from baseline) and PM54 (24% regression from baseline) while the SynSa showed tumor volume stabilization. Both translocation-related models showed significant antitumor effect on histopathological evaluation in response to the novel drugs, compared to trabectedin. Ecubectedin and PM54 have modest antitumor activity in STS PDX models, with the strongest effects seen in the translocation-related sarcoma models, showing the potential of this class of drugs in treatment of STS.