Exploiting the therapeutic efficacy of eribulin in leiomyosarcoma through a better knowledge of its complex mechanism of action

Leiomyosarcoma (LMS) is one of the most common soft tissue sarcomas, representing up to 20% of all of them. Many LMS originate directly from smooth muscle cells or from their precursor showing a predilection for uterus, large blood vessels of retroperitoneum and extremities. Systemic therapies for advanced or metastatic LMS are still a major challenge, with a median survival time of just 1 year. In the phase III trial Eisai-309 the anti-mitotic agent eribulin did not reach a significant difference in progression-free survival and overall survival compared to dacarbazine, the reference drug in this study. However, objective responses were observed in several LMS patients, making the pharmacological effect of this compound worth further investigation. Indeed, eribulin has a complex mechanism of action that includes non-mitotic effects such as differentiation, with increased expression of smooth muscle markers in a LMS cell line. Moreover, eribulin induces the remodelling of tumor vasculature, reducing hypoxia. Unlike vessel normalization induced by antiangiogenics, this phenomenon seems permanent and can lead to improved efficacy of the subsequently administered drugs. Nevertheless, most of this evidence is in vitro or in preclinical models of breast cancer. Demonstrating the relevance of the non-mitotic effect of eribulin in LMS could change the paradigm of its clinical use, not only as a pure cytotoxic agent but also as an adjuvant able to synergize with other drugs. We have recently obtained a panel of LMS patient-derived xenografts (PDXs) that well reproduce the molecular and pathological features of the tumors they derived from. They showed a very heterogeneous response to eribulin treatment representing a good starting point to study the mechanisms of action of this drug. Since molecular heterogeneity is a major determinant of tumor response to specific anticancer agents, we will perform RNAseq studies to identify the pathways involved in sensitivity to or resistance against eribulin, focusing on those related to smooth muscle differentiation. Furthermore, an altered tumor microenvironment may hinder a homogeneous drug distribution in the tumor, thus contributing to a poor pharmacological response. Here we plan to use a in-house Mass Spectrometry Imaging method, to visualize docetaxel in tumor slices obtained from PDX. We will investigate if vessel remodelling induced by a pre-treatment with eribulin could be a possible strategy to improve drug delivery to the neoplastic tissue and consequently its efficacy. Immunohistochemical analysis will be done to assess the drug’s effect on the neoplastic cell and on tumor microenvironment (e.g. necrotic/fibrotic area, vascular remodelling). A better knowledge of the mechanism of action of eribulin will help us to design new strategies to exploit the pharmacological properties of this compound in LMS. Preliminary data supporting possible combinations will be provided at the end of the project.