Abstract 6857: The novel transcriptional inhibitor ecubectedin demonstrates strong antitumor activity in patient-derived xenograft models of soft tissue sarcoma

Abstract Objective: Soft tissue sarcoma (STS) is a heterogenous group of rare, malignant, mesenchymal tumors. Doxorubicin (DOX)-based chemotherapy is standard of care for advanced/metastatic disease, despite low response rates and poor disease control. We explored the antitumor activity of ecubectedin (ECU; PharmaMar), a novel transcriptional inhibitor related to the ecteinascidin family, in patient-derived xenograft (PDX) models of STS, representing sarcomas with complex genomes and translocation-related entities. Methods: ECU was studied in vivo in 6 PDX models, including two leiomyo- (LMS; UZLX-STS22_2, STS111), two dedifferentiated lipo- (DDLPS; STS204, STS112), one synovial (SySa; STS336) and one CIC-rearranged sarcoma (CRS; STS134). Xenografts were transplanted on both flanks of female NMRI nu/nu mice (n=257). Mice were randomized to 5 experimental groups and treated by tail vein injection once weekly: 1) vehicle (VEH) (5% dextrose) 5 mL/kg; 2) DOX 5 mg/kg; 3) trabectedin (TRA) 0.15 mg/kg; 4) lurbinectedin (LUR) 0.18mg/kg; 5) ECU 1.2 mg/kg. Treatment lasted 16 days; antitumor activity was assessed by tumor volume (TV) analysis, histopathology and western blot. Group comparisons used the Mann-Whitney U test, and baseline comparisons used the Wilcoxon test. A p <0.05 was considered statistically significant. Results: ECU-treated tumors were statistically significantly smaller compared to VEH control in all models except STS22_2 on day 16. In 4 out of 6 models the drug caused TV stabilization and in one (STS134) it led to TV shrinkage to 41% compared to baseline. Histopathological analysis confirmed antitumor effects, showing significant changes in mitotic and apoptotic activity compared to VEH-treated tumors (Table 1). Relative tumor volume as compared to baseline Mitotic activity Apoptotic activity Subtypes STS22_2 STS111 STS204 STS112 STS134 STS336 STS22_2 STS111 STS204 STS112 STS134 STS336 STS22_2 STS111 STS204 STS112 STS134 STS336 VEH 349% 155% 205% 273% 387% 259% n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a DOX 243% 170% 148% 154% 177% 161% ↓ ↓ ↓ ↓* ↑* ↑* ↑ ↑* TRA 254% 137% 172% 135% 230% 167% ↓ ↓ ↓ ↓* ↑* ↑* ↑* ↑* LUR 232% 126% 173% 175% 202% 169% ↓* ↓* ↓ ↓* ↑* ↑* ↑* ↑* ECU 181% 104% 143% 104% 41% 97% ↓* ↓* ↓ ↓* ↑* ↑* ↑* ↑* Conclusion: ECU has antitumor effects in PDX models of STS, with the most prominent activity seen in STS134. Next step includes investigating the role of DNA repair mechanisms in response to ECU treatment. Citation Format: Daniel Gorgels, Chao-Chi Wang, Karo Wyns, Lore De Cock, Luna De Sutter, Kimberly Verbeeck, Ulla Vanleeuw, Maria Jose Guillen Navarro, Pablo Manuel Aviles Marin, Agnieszka Wozniak, Patrick Schöffski. The novel transcriptional inhibitor ecubectedin demonstrates strong antitumor activity in patient-derived xenograft models of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6857.