Abstract 1676: Plocabulin, a novel tubulin inhibitor, has antitumor activity in various patient-derived xenograft models of soft tissue sarcoma
Authors: Wang Yannick , Wozniak Agnieszka , Cornillie Jasmien , Lee Che-Jui , Guillén María José , Avilés Pablo , Debiec-Rychter Maria , Sciot Raf , Schöffski Patrick 
Published: September 2020

Objective: Soft tissue sarcomas (STS) constitute a heterogeneous group of rare, malignant tumors arising in mesenchymal tissue. Doxorubicin (DOX)-based chemotherapy has been the standard of care for patients with advanced and metastatic STS, despite providing low response rates and poor disease control in this disease. Even for patients who respond to treatment, the outcome of advanced and metastatic STS is poor. In light of this, there is a clear need for more effective and novel therapeutic compounds for STS. In the current study, we explored the activity of plocabulin (PLO; PM060184, PharmaMar), a novel cytotoxic tubulin-dynamics modifier, in patient-derived xenograft (PDX) models of some common and some rare histologic subtypes of STS.

Methods: Female NMRI nu/nu mice (n=80) were transplanted bilaterally with human STS xenografts: UZLX-STS134CRS (CIC-rearranged sarcoma), UZLX-STS124DDLPS (dedifferentiated liposarcoma), UZLX-STS22_2FLMS (leiomyosarcoma) and UZLX-STS122FIS (intimal sarcoma). Xenografted animals were randomly assigned to three treatment groups: 1) vehicle (20% hydroxypropyl β-cyclodextrin) 6.4 ml/kg intravenously (i.v.) once weekly (QW), 2) DOX 3.0 mg/kg i.v. QW, or 3) PLO 16 mg/kg i.v. QW. All treatments lasted 22 days. Antitumor activity was assessed by tumor volume analysis, histopathology and Western blotting. Mitotic count, phospho-histone H3 and Ki-67 were analyzed for proliferative activity. Apoptotic count, and cleaved poly-(ADP-ribose)-polymerase were analyzed for apoptotic activity. CD31 immunostains were used to evaluate the tumor vasculature. The Kruskal-Wallis test with Dunn's multiple comparisons (DMC) test was used to compare non-parametric variables between groups. Statistical significance was defined as p &lt;0.05.

Results: PLO treatment resulted in tumor shrinkage in UZLX-STS134CRS (to 40% of baseline volume) and UZLX-STS22_2FLMS (to 27%), and tumor volume stabilization in UZLX-STS124DDLPS and UZLX-STS122FIS. Vehicle-treated tumors of UZLX-STS134CRS, UZLX-STS22_2FLMS and UZLX-STS124DDLPS reached 363%, 287% and 261% of baseline volume, respectively. DOX did not affect tumor volume. All DOX-treated mice of UZLX-STS122FIS were lost before the end of the experiment: one mouse was sacrificed on day 16 due to body weight loss, the remaining five were found dead on day 19. Despite this, relative tumor volumes already differed significantly between the vehicle-PLO and DOX-PLO groups on day 16 for this model (p&lt;0.001 and p=0.002, respectively, DMC). PLO-treated tumors of UZLX-STS134CRS and UZLX-STS22_2FLMS were necrotic and degenerated to such an extent that histological analysis could not be performed in full. In the PLO-treated tumors of UZLX-STS122FIS, we demonstrated a significant decrease in the total vascular area, consistent with the drug's vascular disrupting capacity. No effects on proliferation or apoptosis were observed. The experimental drug was well tolerated throughout the experiment at the administered dose.

Conclusion: PLO is a novel anti-tubulin agent showing potent antitumor activity in a variety of PDX modes of STS. The drug induces cytotoxicity mainly through necrosis and is more active than DOX. This study provides strong arguments to study PLO further in STS and to explore the compound in clinical trials involving mesenchymal malignancies.

Citation Format: Yannick Wang, Agnieszka Wozniak, Jasmien Cornillie, Che-Jui Lee, María José Guillén, Pablo Avilés, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. Plocabulin, a novel tubulin inhibitor, has antitumor activity in various patient-derived xenograft models of soft tissue sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1676.