Abstract

Leiomyosarcoma (LMS) is a malignant soft tissue sarcoma (STS) with a dismal prognosis following metastatic disease. Chemotherapeutic intervention has demonstrated to have modest clinical efficacy with no curative potential in LMS patients. Previously, we demonstrated pan-HDAC inhibition to have a superior effect in various complex karyotypic sarcomas. In this study, our goal is to evaluate the therapeutic efficacy of mocetinostat alone and in combination with gemcitabine in LMS. Human leiomyosarcoma (LMS) cell lines were used for in vitro and in vivo studies. Compounds tested included the class I HDAC inhibitor, mocetinostat, and nucleoside analog, gemcitabine. MTS and clonogenic assays were used to evaluate the effect of mocetinostat on LMS cell growth. Cleaved caspase 3/7 analysis was used to determine the effects of mocetinostat on apoptosis. Compusyn software was used to determine in vitro synergy studies for the combination of mocetinostat plus gemcitabine. A LMS xenograft model in SCID mice was used to test the impact of mocetinostat alone, gemcitabine alone and the combination of mocetinostat plus gemcitabine. Mocetinostat abrogated LMS cell growth and clonogenic potential, and enhanced apoptosis in LMS cell lines. The combination of mocetinostat plus gemcitabine exhibited a synergistic effect in LMS cells in vitro. Similarly, mocetinostat combined with gemcitabine resulted in superior anti-LMS effects in vivo. Mocetinostat reduced the expression of gemcitabine-resistance markers RRM1, RRM2, and increased the expression of gemcitabine-sensitivity marker, hENT1, in LMS cells. LMS are aggressive, metastatic tumors with poor prognosis where effective therapeutic interventions are wanting. Our studies demonstrate the potential utility of mocetinostat combined with gemcitabine for the treatment of LMS.

Highlights

  • Leiomyosarcoma (LMS) is a malignant tumor of mesenchymal origin, and is one of the most common soft tissue sarcoma subtypes

  • We previously demonstrated the efficacy of the pan-histone deacetylases (HDAC) inhibitor abexinostat/PCI-24781 on a subset of soft tissue sarcoma (STS) cell lines, including the leiomyosarcoma cell line SKLMS1 [18, 19]

  • LMS1 and Leio-196A demonstrated sensitivity to mocetinostat followed by LMS-117; SKLMS1 and Leio-012 exhibited the highest tolerance among the LMS cells

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Summary

Introduction

Leiomyosarcoma (LMS) is a malignant tumor of mesenchymal origin, and is one of the most common soft tissue sarcoma subtypes. Advanced-stage LMS is usually incurable with current systemic therapies, suggesting the need for novel antitumor strategies [1]. A common LMS systemic therapeutic option includes gemcitabine (2’,2’-difluorodeoxycytidine) combined with docetaxel [3]. Administration of gemcitabine alone was reported to have a response rate of 21% in second-line therapy in uterine LMS based on Gynecological Oncology Group (GOG) response criteria [5]. In a phase II study, gemcitabine combined with docetaxel showed a response rate of 25% by RECIST criteria [6]. Even in the first-line setting, a phase II trial of locally advanced/metastatic LMS demonstrated that gemcitabine combined with docetaxel was active [7]. The combination of gemcitabine and docetaxel are synergistic [8], raising the possibility that gemcitabine be synergistic with other anticancer therapeutics as well

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