Abstract
Simple SummaryDespite advances in both the surgical and medical management of oesophageal adenocarcinoma (OAC), overall prognosis remains poor, with less than 1 in 5 patients surviving more than 5 years from diagnosis. Patients suitable for treatment with curative intent receive pre-operative chemotherapy, but few (<20%) gain a clinically meaningful response. Epigenetic targets have been identified as key drivers in OAC. With therapies targeting histone-modifying enzymes (HME) already in clinical use in several cancer types, they may be a potential novel therapeutic in OAC. This review outlines the current literature surrounding the roles of HMEs in OAC tumorignesis and therapeutic efficacy.Oesophageal adenocarcinoma (OAC) has a dismal prognosis, where curable disease occurs in less than 40% of patients, and many of those with incurable disease survive for less than a year from diagnosis. Despite the widespread use of systematic chemotherapy in OAC treatment, many patients receive no benefit. New treatments are urgently needed for OAC patients. There is an emerging interest in epigenetic regulators in cancer pathogenesis, which are now translating into novel cancer therapeutic strategies. Histone-modifying enzymes (HMEs) are key epigenetic regulators responsible for dynamic covalent histone modifications that play roles in both normal and dysregulated cellular processes including tumorigenesis. Several HME inhibitors are in clinical use for haematological malignancies and sarcomas, with numerous on-going clinical trials for their use in solid tumours. This review discusses the current literature surrounding HMEs in OAC pathogenesis and their potential use in targeted therapies for this disease.
Highlights
This review focuses on the role of Histone-modifying enzymes (HMEs) in Oesophageal adenocarcinoma (OAC) and discusses their potential as novel therapies for this disease
In the two included OAC cell lines (OE33 and SKGT4), histone deacetylases (HDAC) activity was increased compared to a non-neoplastic epithelial cell line (Het-1A), which reflected expression patterns observed in ten case-matched tissue specimens of normal oesophageal epithelium and OAC from neoadjuvant treatment naïve patients
Inhibitors of HMEs are already used in clinical practice for a variety of haematological malignancies, with encouraging results seen in numerous ongoing clinical trials
Summary
Oesophageal cancer is the ninth most common malignancy worldwide, with an estimated global cancer burden of 572,034 cases and 508,585 deaths in 2018 [1] It has a dismal prognosis with less than 20% of patients surviving 5 years after diagnosis [2,3,4]. OAC is highly aggressive and is usually diagnosed at a late stage, mainly due to the delayed nature of symptomatic presentation, with approximately 40% of patients presenting with stage 4 disease [10]. Despite advancements in both the medical and surgical management of OAC, less than 40% of patients are suitable for treatment with curative intent [1,10]. An emerging area of interest is the role of epigenetic regulators in OAC pathogenesis, and these may provide potential novel avenues for future therapy, which we review here
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