Therapeutic options for advanced LPS, particularly WD and/or DD LPS remain extremely limited. The aim of this study was to identify novel therapeutic targets for WDLPS and DDLPS with the working hypothesis that gene products involved in maintaining the undifferentiated phenotype of LPS are potential targets for therapy.
Seven in vitro LPS cell line models of differentiation were established. Forty-nine patient samples derived from primary and matching recurrent, retroperitoneal WDLPS and DDLPS samples, were identified through a search of the Royal Marsden Hospital LPS database. Gene expression profiling of the LPS cell lines and their differentiated counterparts, the patient samples and adipose tissue acting as control, was performed. Differentially expressed genes linked to the differentiation process were identified through bioinformatics analyses, including comparisons with publically available expression data for LPS.
The enhancer of zeste homolog 2 (EZH2) was found to be differentially expressed between WDLPS and DDLPS (higher expression in DDLPS). This differential expression was confirmed at RNA (qRT-PCR) and protein (western blot) levels. Transient reduction of EZH2 levels in LPS cell lines using RNA interference, in combination with a cocktail of agents known to cause differentiation, including steroids and insulin, led to a more differentiated phenotype, which was beyond the level achieved by the differentiation medium alone. The small molecule EZH2 inhibitor (EZH2i) GSK343 decreased cell line growth that was associated with reduction of the histone mark H3K27me3. Combining EZH2i with the differentiation medium resulted in both enhanced differentiation and growth inhibition.
For the first time we demonstrate that inhibition of the epigenetic target EZH2 in WD/DD LPS leads to both enhanced differentiation and growth inhibition in vitro. The efficacy of this dual action is currently being evaluated clinically, in a number of Phase I/ II trials, recruiting patients with solid tumours including those with DDLPS.
Clinical trial identification
Legal entity responsible for the study
The Institute of Cancer Research
Wellcome Trust UK
All authors have declared no conflicts of interest.