Targeting abundant survivin expression in liposarcoma: subtype dependent therapy responses to YM155 treatment

Christian Vay,Philipp M Schlünder,Irene Esposito,Markus P H Ghadimi,Levent Dizdar,Andreas Krieg,Wolfram T Knoefel

doi:10.1007/s00432-021-03871-5

Abstract

PurposeLiposarcoma (LPS) represent the largest group of malignant soft tissue tumours comprising a heterogeneous group of subtypes in which the degrees of chemoresistance and radiosensitivity strongly vary. Consequently, it is of utmost interest to establish novel therapeutic regimens based on molecular targets.MethodsImmunohistochemical staining of survivin was performed in tissue microarrays comprising 49 primary LPS specimens. LPS cell lines were treated with survivin antagonist YM155 and doxorubicin or etoposide alone as well as in combination. Changes in cell viability were investigated and the synergistic effect of a combined therapy analysed.ResultsImmunohistochemistry revealed an abundant expression of survivin in LPS that significantly concurred with less-differentiated tumour subtypes and grading. In vitro, we demonstrated the impact of the survivin inhibitor YM155 on dedifferentiated LPS (DDLPS) and, even more imposing, pleomorphic LPS (PLS) tumour cell viability with a strong induction of apoptosis. A combined treatment of doxorubicin or etoposide with YM155 augmented the cytotoxic effects on DDLPS and PLS cells.ConclusionThese findings support the significant role of survivin in the oncogenesis and progression of LPS subtypes providing a rationale to target survivin in eligible in-vivo models and to pioneer clinical applications of survivin-specific substances unfolding their therapeutic potential in LPS patients prospectively.

Highlights

IntroductionLiposarcoma (LPS) is among the most frequent types of soft tissue sarcoma with 50% of retroperitoneal localisation and 25% peripheral distribution (Crago and Brennan 2015).Complete surgical resection is the central therapeutic approach towards all four main groups of LPS—wellSharing their fate of significant recurrence levels and a perspective of limited patient survival after surgery in a serious proportion of LPS patients, the various subtypes differ with regard to their biological attributes (Dalal et al 2006; Lee et al 2018)
Assessing the clinicopathologic parameters statistically, LPS affecting the deep soft tissue in the abdomen and retroperitoneum, which was to be distinguished from LPS localised within the superficial soft tissue of the head, extremities, or thorax, correlated with LPS subtypes pleomorphic liposarcoma (PLS)/ dedifferentiated liposarcomas (DDLPS) (p = 0.037; Cramér’s V = 0.417), higher tumour grade (p = 0.037; Cramér’s V = 0.417) and larger primary tumour size (T3/4) (p = 0.016; Cramér’s V = 0.344)
In this study we demonstrated that survivin expression correlated with tumour subtype and grading in LPS

Summary

Introduction

Liposarcoma (LPS) is among the most frequent types of soft tissue sarcoma with 50% of retroperitoneal localisation and 25% peripheral distribution (Crago and Brennan 2015).Complete surgical resection is the central therapeutic approach towards all four main groups of LPS—wellSharing their fate of significant recurrence levels and a perspective of limited patient survival after surgery in a serious proportion of LPS patients, the various subtypes differ with regard to their biological attributes (Dalal et al 2006; Lee et al 2018). Liposarcoma (LPS) is among the most frequent types of soft tissue sarcoma with 50% of retroperitoneal localisation and 25% peripheral distribution (Crago and Brennan 2015). Complete surgical resection is the central therapeutic approach towards all four main groups of LPS—well. Sharing their fate of significant recurrence levels and a perspective of limited patient survival after surgery in a serious proportion of LPS patients, the various subtypes differ with regard to their biological attributes (Dalal et al 2006; Lee et al 2018). With more complex genomic aberrations frequently altering chromosomes 3, 11, and 19 (Crago et al 2012), DDLPS stands out with a disease-specific 5-year-survival of 44%. As 30–50% of PLS patients develop local tumour relapse and up to 50%

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