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Zoe Walters
University of Southampton, UK
Posters & Accepted Abstracts: J Can Res Metastasis
Differentiation therapy is an approach that has had notable success in a limited number of cancer types including acute promyelocytic leukaemia and neuroblastoma but remains underexplored for most tumour types. Therapeutic drugs have been shown to promote differentiation in preclinical models including soft tissue sarcomas (STS) that often resemble undifferentiated mesenchymal tissues. Rhabdomyosarcomas (RMS) are the most common paediatric STS and appear as developing skeletal muscle that are unable to terminally differentiate through aberrant recapitulation of developmental programs.
Histone modifications are known to govern these developmental programs by controlling activities such as DNA transcription and cell differentiation. Enhancer of Zeste Homolog 2 (EZH2) confers histone methyltransferase activity to the Polycomb Repressive Complex 2 (PRC2), and is known to control stem cell renewal and differentiation. We have shown that EZH2 and other members of the Polycomb Repressive Complex 2 (PRC2) play a role in the differentiation program of RMS and are required to maintain the undifferentiated phenotype of these tumours. Single agent modulation of EZH2 using a tool compound or clinical drug candidate results in modest differentiation of RMS cell lines, a phenotype that we show is augmented by combination with differentiating agents in vitro. Furthermore, we show that this combination can also be used to effectively reduce proliferation in synovial sarcoma lines in vitro. Thus combining inhibition of histone modifying enzymes with differentiating agents or other frontline therapies already in clinical use represent a novel potential avenue for therapeutic intervention for use in the treatment of STS.
E-mail: Z.S.Walters@soton.ac.uk
+44 7362049920
