Anti-Tumour Treatment Epigenetic therapy and chemosensitization in solid malignancy Sean M. Ronnekleiv-Kelly, Anup Sharma, Nita Ahuja ⇑ Department of Surgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA article info Article history: Received 31 October 2016 Received in revised form 21 March 2017 Accepted 23 March 2017 Keywords: Epigenetics Cancer Solid tumors Epigenetic therapy Chemosensitization abstract Epigenetic modifications result in dynamic shifts between transcriptionally active and suppressed states. The potentially reversible nature of epigenetic changes underlies the concept of epigenetic therapy, which serves to reprogram cancer cells as opposed to inducing cytotoxicity that occurs with standard chemotherapeutics. There are numerous enzymes involved in epigenetic changes and each can be potentially targetable. Although many investigations have evaluated the clinical potential of the various epigenetic therapies, currently only histone deacetylase inhibitors and DNA methyltransferase inhibitors are approved for use in specific hematologic malignancies. Use of epigenetic therapy coincident with cytotoxic or targeted systemic therapy appears to derive a benefit due to chemosensitization. Trials demonstrating efficacy from combination therapy have been performed in various diseases such as NSCLC, ovarian cancer and breast cancer. Furthermore, there are patient subsets in certain solid tumors in which epigenetic therapy provide durable response, such as patients with NSCLC and specific hypermethylation patterns. The encouraging results from combination therapy identified in these trials built upon prior investigations and have provided a foundation for ensu- ing trials seeking to evaluate epigenetic therapy. Ó 2017 Elsevier Ltd. All rights reserved. Introduction The remarkable diversity of malignant processes underlies the difficulty in elucidating pathophysiology of and treatment for can- cer. As eloquently outlined by Hanahan and Weinberg, a number of traits are acquired in the transformation from normal cell to neo- plastic process, including sustained growth promoting signaling, circumventing apoptosis, immune evasion, and suppression of tumor suppressor genes [1]. These changes may occur via somatic mutations; alternatively, they can arise from epigenetic modifica- tion. For instance, cancer cells can achieve sustained proliferative stimulation via mutation in phosphatase and tensin homolog (PTEN), resulting in loss of function and amplification of PI3K sig- naling; similarly, PTEN expression can be inhibited by promoter methylation, which is a form of epigenetic modification [1]. Initially, epigenetic changes were found to be integral to malig- nant processes through a series of gene expression and DNA methylation studies [2]. Many of the early studies did not establish mechanism or pathways, but did identify a potential correlation between epigenetic modifications and cancer. With improved understanding of epigenetics, it has become clear that genetic and epigenetic changes are concomitantly involved in cancer initi- ation, promotion and progression. Affirming this concept is the fact that there have been identified a number of genetic lesions in epi- genetic regulators in nearly all tumor types [3,4]. The ensuing aber- rant signaling from these epigenetic regulators can then further promote gene expression alterations through modification of his- tone structure. Epigenetics encompasses the heritable phenotype that arises from covalent modifications in histones and DNA without alter- ations of the DNA sequence itself [5,6]. Signals that initiate epige- netic changes may be an environmental cue, internal stimuli or developmental signals. Following the initial input, signal transduc- tion incites a protein or noncoding RNA to establish chromatin interaction at a specific location, followed by a sustained chro- matin state [5]. The chromatin-DNA interaction influences chro- matin configuration; the presence of DNA in nucleosome- depleted regions is associated with gene expression while tightly bound DNA in the nucleosome structure leads to gene repression [7,8]. Nucleosomes consist of DNA wrapped around eight core his- tone proteins (2 each of H2A, H2B, H3 and H4), and post- translational modification of these core histones includes histone acetylation, methylation, ubiquitination, sumoylation, and phos- phorylation; each can change the nucleosome structure, resulting http://dx.doi.org/10.1016/j.ctrv.2017.03.008 0305-7372/Ó 2017 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: Department of Surgery, Johns Hopkins Hospital, 600 N. Wolfe Street, Blalock 685, Baltimore, MD 21287, USA. Fax: +1 (443) 451 8583. E-mail address: nahuja1@jhmi.edu (N. Ahuja). Cancer Treatment Reviews 55 (2017) 200–208 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv