Abstract 1880: Ecubectedin and PM54 demonstrate antitumor activity in patient-derived xenograft models of soft tissue sarcoma
Authors: Gorgels Daniël , Wozniak Agnieszka , Wang Chao-Chi , Avilés Pablo M. , Guillen Maria J. , Cuevas Carmen , Schöffski Patrick 
Published: March 2024

Abstract
Objective: Soft tissue sarcoma (STS) is a heterogenous group of rare, malignant tumors arising from mesenchymal tissue. Doxorubicin (DOX)-based chemotherapy is the standard for advanced or metastatic STS, despite low response rates and poor disease control. We explored the antitumor activity of two novel compounds, ecubectedin (ECU; PM14) and PM54 (PharmaMar), in two patient-derived xenograft (PDX) models of STS, leiomyosarcoma (LMS) and CIC-rearranged sarcoma (CRS). Mode of action of ECU and PM54 is similar to lurbinectedin (LUR), inhibiting oncogenic transcription by eviction of oncogenic transcription factors from gene promotors’ recognition sequences, while inducing the generation of double strand breaks through DNA adduct formation.
Methods: Female NMRI nu/nu mice (n=104) were transplanted bilaterally with STS PDX: UZLX-STS134 (CRS) and UZLX-STS22_2 (LMS). Xenografted mice were randomized to six treatment groups: 1) vehicle (VEH) (5% dextrose) 5 mL/kg once weekly (QW) intravenously (IV); 2) DOX 5 mg/kg QW IV; 3) trabectedin (TRA) 0.15 mg/kg QW IV; 4) LUR 0.18 mg/kg QW IV; 5) ECU 1.2 mg/kg QW IV; 6) PM54 1.2 mg/kg QW IV. Treatment lasted 16 days and 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 to baseline.
Results: ECU and PM54 caused TV shrinkage in UZLX-STS134, while TV in other groups grew significantly on day 16 (Table 1). VEH treatment led to the largest TV increase on day 16, compared to any treatment. PM54 treatment showed TV stabilization in UZLX-STS22_2, and significantly smaller tumors than VEH and TRA treated tumors (p&lt;0.05 and p&lt;0.01,
respectively). Histopathological evaluation corroborate the results from the relative TV analysis.
Conclusion: Novel drugs exhibit promising results in the PDX models tested, supporting ongoing exploration in additional PDX models of synovial sarcoma and dedifferentiated liposarcoma.
Table 1: TV change on day 16 versus baseline, and comparison of proliferative and apoptotic activity Tumor volume change Proliferative activity (pHH3) Apoptotic activity (cPARP) Subtypes UZLX-STS134 UZLX-STS22_2 UZLX-STS134 UZLX-STS22_2 UZLX-STS134 UZLX-STS22_2 VEH(5 ML/kg) 387%*** 349%** n/a n/a n/a n/a DOX (5 mg/kg/QW IV) 177%*** 243%** ↓*** ↓ ↑** ↑ TRA(0.15 mg/kg/QW IV) 230%** 254%*** ↓** ↓** ↑** ↑*** LUR(0.18 mg/kg/QW IV) 202%** 232%** ↓*** ↓*** ↑*** ↑** ECU(1.2 mg/kg/QW IV) 41%*** 181%** ↓*** ↓*** ↑*** ↑*** PM54 (1.2 mg/kg/QW IV) 76%*** 162% ↓*** ↓*** ↑*** ↑
Citation Format: Daniël Gorgels, Agnieszka Wozniak, Chao-Chi Wang, Pablo M. Avilés, Maria J. Guillen, Carmen Cuevas, Patrick Schöffski. Ecubectedin and PM54 demonstrate antitumor activity in patient-derived xenograft models of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1880.