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Epigenetic modulation in well differentiated (WD) and dedifferentiated (DD) liposarcoma (LPS): a novel therapeutic approach

Date

10 Oct 2016

Session

Sarcoma

Presenters

Anastasia Constantinidou

Citation

Annals of Oncology (2016) 27 (6): 483-492. 10.1093/annonc/mdw388

Authors

A. Constantinidou1, J. Selfe2, T. Khin3, S. Popov2, E. Missiaglia4, E. Aladowicz2, R. Al-Saadi2, D. Olmos5, R.L. Jones6, D.C. Strauss7, A. Hayes7, W. van der Graaf6, I. Judson6, J. Shipley2

Author affiliations

  • 1 Molecular Pathology, Institute of Cancer Research ICR, SM2 5NG - London/GB
  • 2 Molecular Pathology, Institute of Cancer Research ICR, London/GB
  • 3 Histopathology, Royal Marsden Hospital NHS Foundation Trust, London/GB
  • 4 Swiss Institute Of Bioinformatics, Swiss Institute of Bioinformatics, Lausanne/CH
  • 5 Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid/ES
  • 6 Sarcoma Unit, Royal Marsden Hospital, London/GB
  • 7 Melanoma/sarcoma Unit, Department Of Surgery, The Royal Marsden Hospital, London/GB
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Resources

Abstract 2559

Background

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.

Methods

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.

Results

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.

Conclusions

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

Funding

Wellcome Trust UK

Disclosure

All authors have declared no conflicts of interest.

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