新型微管蛋白抑制剂PM534在软组织肉瘤患者来源异种移植模型中具有抗肿瘤活性

Objective: Soft tissue sarcoma (STS) is an heterogenous group of rare, malignant, mesenchymal tumors. Doxorubicin (DOX)-based chemotherapy is standard of care for advanced/metastatic disease, despite significant toxicity, low response rates and poor disease control. Trabectedin (TRA) is a second-line treatment for liposarcoma (LPS) and leiomyosarcoma (LMS), with clinical activity seen also in other subtypes. We explored the antitumor activity of PM534 (PharmaMar, Spain), a novel tubulin inhibitor, in patient-derived xenograft (PDX) models of STS. Methods: Female NMRI nu/nu mice (n=92) were transplanted bilaterally with UZLX-STS149 LMS , UZLX-STS22 LMS (LMS) and UZLX-STS112 DDLPS (dedifferentiated liposarcoma - DDLPS). Mice were randomized to 4 treatment groups, receiving treatment once weekly via tail vein injection 1) vehicle (VEH) 5 mL/kg; 2) DOX 5 mg/kg; 3) trabectedin (TRA) 0.15 mg/kg; 4) PM534 4.75mg/kg. Treatment lasted 16 days and antitumor activity was assessed by tumor volume (TV) analysis, histopathology (markers for proliferation and apoptosis), validated by western blot. The Mann-Whitney U test was used to compare groups on the last day of experiment, the Wilcoxon test to compare the TV evolution during the experiment per group (day 1 vs day 16). Statistical significance was defined as p <0.05. Results: In UZLX-STS22 LMS and -112 DDLPS treatment with PM534 led to TV stabilization (growth to 156% and 133% on day 16 as compared to baseline). In UZLX-STS149 LMS the compound led to tumor growth delay (289% vs 644% in untreated controls; p=0.0039). The antitumor effect in all models was significantly better than in vehicle-treated mice, while in UZLX-STS22 LMS and -STS112 DDLPS PM534 outperformed DOX. Histopathology showed a high degree of necrosis in PM534-treated tumors, and the drug had strong anti-proliferative and pro-apoptotic activity, as assessed with hematoxylin and eosin staining. Both DOX and TRA led to a moderate inhibition of mitosis as compared to untreated controls. PM534 was well tolerated throughout the experiment at the dose administered, while TRA showed some degree of local toxicity at the site of administration. The completed histopathological analysis and western blotting will be reported at the meeting and the efficacy of PM534 will now be explored in additional models. Conclusion: PM534 has strong antitumor effects in PDX models of LMS and DDLPS, outperforms the in vivo efficacy of treatment with standard agents and should be further evaluated in the preclinical and clinical setting.