(P 33) THE NOVEL TRANSCRIPTIONAL INHIBITORS ECUBECTEDIN AND PM54 DEMONSTRATE ANTITUMOR ACTIVITY IN PATIENT-DERIVED XENOGRAFT MODELS OF SOFT TISSUE SARCOMA

Objective: We explored the antitumor activity of two novel transcription inhibitors, ecubectedin (ECU) and PM54, derivatives of lurbinectedin (LUR), under development by PharmaMar (Spain). ECU and PM54 inhibit oncogenic transcription by displacing transcription factors from gene promotors and inducing double strand breaks through DNA adduct formation, replicating the cytotoxic effects of natural ecteinascidins.

Methods: The experimental compounds were tested in 6 patient-derived xenograft (PDX) models of soft tissue sarcoma (STS): two leiomyosarcomas (UZLX-STS22_2 and STS111), two dedifferentiated liposarcomas (STS204 and STS112), one CIC-rearranged sarcoma (STS134) and one synovial sarcoma (STS336) model. Female NMRI nu/nu mice (n=52/experiment) were transplanted subcutaneously bilaterally with respective PDX models. An additional 52 mice were transplanted with model STS336 to investigate a potential survival benefit after treatment had stopped. Xenografted mice were randomized to 6 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/kg 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: ECU and PM54 caused tumor shrinkage (p < 0.05) in STS134 (Table 1), while other treatments led to tumor growth on day 16. ECU-treated tumors were statistically significantly smaller compared to VEH control in all other models except STS22_2 on day 16. PM54-treated tumors showed TV stabilization in all other models on day 16. In STS336 Both ECU- and PM54-treated tumors displayed prolonged TV stabilization up to 26 days after the last treatment. Histopathological analysis of collected tumor material showed the strongest antitumor effect with the novel drugs in all models as compared to other treatments.

Conclusion: The novel compounds ECU and PM54 consistently showed the strongest antitumor activity in the PDX models tested, achieving prolonged TV-stabilization in STS336 even after treatment cessation. In ongoing experiments we are now exploring the impact of the DNA repair capacity of the models on the antitumor effects observed with the drugs.

Tumor volume change on day 16 and comparison of mitotic and apoptotic activity of respective treatment groups compared to vehicle on day 16. ↓ decrease in activity, as compared to baseline. ↑ increase in activity. VEH: vehicle; DOX: doxorubicin; TRA: trabectedin; LUR; lurbinectedin; n/a: not applicable (*p < 0.05).