title: Investigational epigenetically targeted drugs in early phase trials for the treatment of haematological malignancies.
abstract: BACKGROUND
  For decades, cancer research has focussed on the genetic defects that drive tumourigenesis. However, recent high-resolution sequencing studies have uncovered mounting evidence for the complementary role of epigenetic deregulation as a hallmark of haematological malignancies. The reversibility of epigenetic changes makes them suitable candidates for pharmacological manipulation and therapeutic targeting.
  
  
  METHODS
  This review summarises the mechanisms of normal epigenetic regulation and how these are perturbed in haematological malignancies as a result of genetic alterations. The article concludes with how these can be reversed and appraises the investigational epigenetically targeted therapies in preclinical and clinical use.
  
  
  CONCLUSIONS
  The identification of recurring alterations in components of the epigenome of leukaemia and lymphoma has driven the rapid development of highly potent epigenetically targeted therapies. This rapid development has alluded to the possibility of a personalised therapeutic approach in selected patient populations. An enhanced understanding of the biological effects of these epigenetic alterations in initiation and progression of haematological malignancies, together with a clear mechanistic insight into how the drugs reverse the phenotypes, will define their translation into routine clinical use.
authors.affiliation: Queen Mary University of London, Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Centre for Haemato-Oncology, John Vane Science Centre , Charterhouse Square, London EC1M 6BQ , UK +44 20 7882 8780 ; +44 20 7882 3891 ; j.e.okosun@qmul.ac.uk.
authors.forename: Jessica
authors.initials: J
authors.lastname: Okosun
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.forename: Jude
authors.initials: J
authors.lastname: Fitzgibbon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D018450:Disease Progression; D015195:Drug Design; D015507:Drugs, Investigational / Q000494:pharmacology; D044127:Epigenesis, Genetic; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational
keywords: DOT1L inhibitor; bromodomain and extra-terminal; enhancer of zeste homolog 2 inhibitor; epigenetics; inhibitor; isocitrate dehydrogenase inhibitor; leukaemia; lymphoma