Abstract 6858: The next generation transcriptional inhibitor PM54 demonstrates strong antitumor activity in patient-derived xenograft models of soft tissue sarcoma
Authors: 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
Journal: Cancer Research (2025)

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 STS, despite low response rates and poor disease control. We explored the antitumor activity of PM54 (PharmaMar), a next generation transcriptional inhibitor related to the ecteinascidin family of agents, in patient-derived xenograft (PDX) models of STS. Methods: Female NMRI nu/nu mice (n=258) were transplanted on both flanks with 6 different PDX models of leiomyo- (LMS; UZLX-STS22_2, STS111), dedifferentiated lipo- (DDLPS; STS204, STS112), CIC-rearranged (CRS; STS134) and synovial sarcoma (SySa; STS336). Mice were randomized to 5 treatment 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) 0.18 mg/kg; 5) PM54 1.2 mg/kg. Treatment lasted 16 days. Antitumor activity was assessed by tumor volume (TV) analysis, histopathology and western blot. The Mann-Whitney U test was used to compare groups, the Wilcoxon test to compare with baseline. A p value of &amp;lt;0.05 was considered statistically significant. Results: PM54-treated tumors were statistically significantly smaller when compared to VEH-treated PDX on day 16. TV stabilization on day 16 was seen in 5 out of 6 models, while in STS134 the experimental compound led to TV shrinkage to 76% of the baseline (table 1). Histopathological analysis supported the TV analysis showing that PM54 exerted the strongest antitumor effect in all models analyzed thus far, compared to VEH-treated tumors. 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 Vehicle 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% ↓* ↓* ↓* ↓* ↑* ↑* ↑* ↑* PM54 162% 113% 145% 125% 76% 100% ↓* ↓* ↓* ↓* ↑* ↑* ↑* ↑* Conclusion: PM54 has strong antitumor activity in PDX models of STS, with the most pronounced effects in STS134. Further steps include investigation of the role of DNA repair mechanisms in response to treatment with PM54 and the clinical development of this next generation transcriptional inhibitor in STS. 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 next generation transcriptional inhibitor PM54 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 6858.