title: Epigenetic Therapy for Solid Tumors: Highlighting the Impact of Tumor Hypoxia.
abstract: In the last few decades, epigenetics has emerged as an exciting new field in development and disease, with a more recent focus towards cancer. Epigenetics has classically referred to heritable patterns of gene expression, primarily mediated through DNA methylation patterns. More recently, it has come to include the reversible chemical modification of histones and DNA that dictate gene expression patterns. Both the epigenetic up-regulation of oncogenes and downregulation of tumor suppressors have been shown to drive tumor development. Current clinical trials for cancer therapy include pharmacological inhibition of DNA methylation and histone deacetylation, with the aim of reversing these cancer-promoting epigenetic changes. However, the DNA methyltransferase and histone deacetylase inhibitors have met with less than promising results in the treatment of solid tumors. Regions of hypoxia are a common occurrence in solid tumors. Tumor hypoxia is associated with increased aggressiveness and therapy resistance, and importantly, hypoxic tumor cells have a distinct epigenetic profile. In this review, we provide a summary of the recent clinical trials using epigenetic drugs in solid tumors, discuss the hypoxia-induced epigenetic changes and highlight the importance of testing the epigenetic drugs for efficacy against the most aggressive hypoxic fraction of the tumor in future preclinical testing.
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK. shaliny.ramachandran@oncology.ox.ac.uk.
authors.forename: Shaliny
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK. jonathan.ient@oncology.ox.ac.uk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ient
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK. el.gottgens@gmail.com.
authors.forename: Eva-Leonne
authors.initials: EL
authors.lastname: Göttgens
authors.affiliation: Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA. akrieg@kumc.edu.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Krieg
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK. Ester.Hammond@oncology.ox.ac.uk.
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
keywords: DNA methylation; epigenetic drugs; gene-repression; histone deacetylation; histone methylation; tumor hypoxia