Plocabulin, a Novel Tubulin Inhibitor, Has Potent Antitumour Activity in Patient-Derived Xenograft Models of Soft Tissue Sarcoma.

A clinically relevant subset of patients with soft tissue sarcoma presents with either locally advanced or upfront metastatic disease, or will develop distant metastases over time, despite successful treatment of their primary tumour. The currently available systemic agents to treat such advanced cases only provide modest disease control and are not active in all histological subtypes. Thus, there is an unmet need for novel and more efficacious agents to improve the outcome of this rare disease. In the current preclinical in vivo study, we evaluated plocabulin, a novel tubulin inhibitor, in five distinct histological subtypes of soft tissue sarcoma: dedifferentiated liposarcoma, leiomyosarcoma, undifferentiated sarcoma, intimal sarcoma and CIC-rearranged sarcoma. The efficacy was tested in seven patient-derived xenograft models, which were generated by the engraftment of tumour fragments from patients directly into nude mice. The treatment lasted 22 days, and the efficacy of the drug was assessed and compared to the doxorubicin and vehicle groups by volumetric analysis, histopathology and immunohistochemistry. We observed tumour volume control in all the tested histological subtypes. Additionally, in three sarcoma subtypes, extensive central necrosis, associated with significant tumour regression, was seen. This histological response is explained by the drug's vascular-disruptive properties, reflected by a decreased total vascular area in the xenografts. Our results demonstrate the in vivo efficacy of plocabulin in the preclinical models of soft tissue sarcoma and corroborate the findings of our previous study, which demonstrated similar vascular-disruptive effects in gastrointestinal stromal tumours-another subtype of soft tissue sarcoma. Our data provide a convincing rationale for further clinical exploration of plocabulin in soft tissue sarcomas.

Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors.

The majority of patients with gastrointestinal stromal tumors (GIST) eventually become resistant with time due to secondary mutations in the driver receptor tyrosine kinase. Novel treatments that do not target these receptors may therefore be preferable. For the first time, we evaluated a tubulin inhibitor, plocabulin, in patient-derived xenograft (PDX) models of GIST, a disease generally considered to be resistant to cytotoxic agents. Three PDX models of GIST with different KIT genotype were generated by implanting tumor fragments from patients directly into nude mice. We then used these well characterized models with distinct sensitivity to imatinib to evaluate the efficacy of the novel tubulin inhibitor. The efficacy of the drug was assessed by volumetric analysis of the tumors, histopathology, immunohistochemistry and Western blotting. Plocabulin treatment led to extensive necrosis in all three models and significant tumor shrinkage in two models. This histological response can be explained by the drug's vascular-disruptive properties, which resulted in a shutdown of tumor vasculature, reflected by a decreased total vascular area in the tumor tissue. Our results demonstrated the in vivo efficacy of the novel tubulin inhibitor plocabulin in PDX models of GIST and challenge the established view that GIST are resistant to cytotoxic agents in general and to tubulin inhibitors in particular. Our findings provide a convincing rationale for early clinical exploration of plocabulin in GIST and warrant further exploration of this class of drugs in the management of this common sarcoma subtype.

Establishment and Characterization of Histologically and Molecularly Stable Soft-tissue Sarcoma Xenograft Models for Biological Studies and Preclinical Drug Testing.

Soft-tissue sarcomas (STS) represent a heterogeneous group of rare, malignant tumors of mesenchymal origin. Reliable in vivo sarcoma research models are scarce. We aimed to establish and characterize histologically and molecularly stable patient-derived xenograft (PDX) models from a broad variety of STS subtypes. A total of 188 fresh tumor samples from consenting patients with localized or advanced STS were transplanted subcutaneously in NMRI-nu/nu-immunodeficient mice. Once tumor growth was observed, the material was passaged to a next generation of mice. A patient-derived tumor sample was considered "successfully engrafted" whenever the sample was transplanted to passage 1. A PDX model was considered "established" when observing stable morphologic and molecular features for at least two passages. With every passage, histologic and molecular analyses were performed. Specific genomic alterations and copy-number profile were assessed by FISH and low coverage whole-genome sequencing. The tumor engraftment rate was 32% (61/188) and 188 patient samples generated a total of 32 PDX models, including seven models of myxofibrosarcoma, five dedifferentiated liposarcoma, five leiomyosarcoma, three undifferentiated pleomorphic sarcoma, two malignant peripheral nerve sheet tumor models, and single models of synovial sarcoma and some other (ultra)rare subtypes. Seventeen additional models are in early stages of engraftment (passage 1-2). Histopathologic and molecular features were compared with the original donor tumor and were stable throughout passaging. The platform is used for studies on sarcoma biology and suited for in vivo preclinical drug testing as illustrated by a number of completed and ongoing laboratory studies.