Antitumor Activity of Novel Transcriptional Inhibitors Ecubectedin and PM54 in Soft Tissue Sarcoma Patient-Derived Xenografts.

UNLABELLED: 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 Naval Medical Research Institutenu/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 (i) vehicle, (ii) doxorubicin, (iii) trabectedin, (iv) lurbinectedin, (v) ecubectedin, or (vi) 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 posttreatment xenograft evolution. Antitumor activity was assessed by tumor volume measurement, histopathologic, and immunohistochemical analyses. In all LMS and DDLPS models, ecubectedin and PM54 led to tumor growth delay compared with trabectedin. Histopathologic evaluation of treated tumors showed moderately increased antitumor activity of novel ecteinascidins compared with trabectedin. The CRS model showed tumor shrinkage in response to ecubectedin (63% regression from baseline) and PM54 (24% regression from baseline), while the SynSa model showed tumor volume stabilization. Both translocation-related models showed significant antitumor effect on histopathologic evaluation in response to the novel drugs compared with 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 the treatment of STS.

SIGNIFICANCE: Advanced STS remains without truly effective therapeutic options. Translocation-related sarcomas demonstrate higher vulnerability to next-generation ecteinascidin treatment compared with more complex sarcoma subtypes. This vulnerability builds upon known literature and could be exploited in future clinical trials using the next-generation ecteinascidins.