(P 340) THE DNA MINOR GROOVE BINDING AGENTS ECUBECTEDIN AND PM54 DEMONSTRATE ANTITUMOR ACTIVITY IN PATIENT-DERIVED XENOGRAFT MODELS OF SOFT TISSUE SARCOMA

Objective: We explored the antitumor activity of two DNA minor groove binding derivatives of lurbinectedin (LUR), under development by PharmaMar (Spain): ecubectedin (ECU) and PM54, in four patient-derived xenograft (PDX) models of soft tissue sarcoma (STS). Two leiomyosarcoma (LMS), one CIC-rearranged sarcoma (CRS), and one dedifferentiated liposarcoma (DDLPS). ECU and PM54 replicate the cytotoxic effect of natural ecteinascidins. Additionally, they inhibit oncogenic transcription by displacing transcription factors from gene promotors and inducing double strand breaks through DNA adduct formation.

Methods: Female NMRI nu/nu mice (n=52/experiment) were transplanted bilaterally with PDX models UZLX-STS22_2LMS and STS111LMS, STS134CRS or STS204DDLPS. Xenografted mice were randomized to six treatment groups: 1) vehicle (VEH) (5% dextrose) 5 mL/kg once weekly (QW) intravenously (IV); 2) doxorubicin (DOX) 5mg/kg QW IV; 3) trabectedin (TRA) 0.15 mg/kg QW IV; 4) LUR 0.18 mg/kg QW IV; 5) ECU 1.2mg/kg QW IV; 6) PM54 1.2 mg/kw QW IV. Treatment lasted 16 days and antitumor activity was assessed by tumor volume (TV) and histopathology. The Mann-Whitney U test and the Wilcoxon test were used to compare the treatment effect to baseline values and between groups, respectively.

Results: In STS134CRS ECU and PM54 treatment caused TV decrease (p< 0.001), while tumors in other groups grew significantly on day 16 (Table 1). STS22_2LMS tumors treated with PM54 showed TV stabilization and significantly smaller tumors than VEH and TRA treated tumors (p< 0.05 and (p< 0.01, respectively). STS111LMS tumors treated with ECU showed TV stabilization. In STS204DDLPS, both ECU and PM54 treated tumors showed the strongest antitumor effect, compared to all other treatments. Histopathological evaluation of STS134CRS and STS22_2LMS showed a significant increase in apoptotic cells, and a significant decrease in mitotic cells in both ECU and PM54 treated tumors (p< 0.001). The histopathological analysis for STS111LMS and STS204DDLPS is ongoing.

Conclusion: The novel compounds ECU and PM54 have antitumor activity in the PDX models tested here. We are now exploring the agents in additional PDX models of synovial sarcoma and DDLPS. We will also study the impact of the DNA repair capacity of the models on the antitumor effects observed with the drugs.