Mechanisms of Sensitivity and Resistance to Epigenetic Therapies

Our expanding knowledge of cancer genomes and epigenomes has highlighted the critical role that aberrant epigenetic regulation plays in the pathogenesis of many hematological malignancies. Central to this issue are the perturbation of chemical modifications of histones and DNA, so called epigenetic modifications. Epigenetic modifications are dynamically deposited, removed and ‘read’ by highly conserved enzymes and adaptor proteins respectively. The information conveyed by these modifications is essential in directing all the DNA based processes such as transcription, DNA repair and replication. Consequently, when these epigenetic enzymes or readers are mutated they may culminate in the induction and/or maintenance of various cancers. Importantly, the dynamic plasticity of the epigenome lends itself well to therapeutic manipulation and as such the last decade has witnessed an unprecedented investment in the development and application of targeted epigenetic therapies. In this session, I will provide an overview of the new epigenetic therapies currently in early clinical trials. I will focus on the pre-clinical evidence for the potential molecular and cellular mechanisms that result in therapeutic efficacy. I will also highlight the developing evidence for how therapeutic resistance may emerge to these novel targeted therapies.