The role of epigenetic therapies in colorectal cancer |
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| Institution: | 1. Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;2. Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;1. Cancer Center and Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Str., Zhengzhou 450052, China;2. The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute, Griffith University, Queensland, Australia;3. Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, SA 5042, Australia;4. Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1, Severnii pr., Chernogolovka 142432, Russia;5. Department of Human Anatomy, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Trubetskaya Street, Moscow 119991, Russia;6. Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Academy of Higher Education and Research (JSS AHER), JSS Medical College, Mysuru, Karnataka, India;7. Translational Research Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, Tamil Nadu 641046, India;1. Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia;2. Discipline of Biology, College of Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia;3. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany;4. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia;5. Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia;6. Federal State Budgetary Institution «Research Institute of Human Morphology», 3, Tsyurupy Str., Moscow, 117418, Russian Federation;7. GALLY International Research Institute, San Antonio, TX, 78229, USA;1. Olivia Newton-John Cancer Research Institute, Melbourne, Australia;2. School of Cancer Medicine, La Trobe University, Melbourne, Australia;3. These authors contributed equally |
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| Abstract: | Although developments in the diagnosis and therapy of colorectal cancer (CRC) have been made in the last decade, much work remains to be done as it remains the second leading cause of cancer death. It is now well established that epigenetic events, together with genetic alterations, are key events in initiation and progression of CRC. Epigenetics refers to heritable alterations in gene expression that do not involve changes in the DNA sequence. These alterations include DNA methylation, histone alterations, chromatin remodelers, and noncoding RNAs. In CRC, aberrations in epigenome may also involve in the development of drug resistance to conventional drugs such as 5-fluorouracil, oxaliplatin, and irinotecan. Thus, it has been suggested that combined therapies with epigenetic agents may reverse drug resistance. In this regard, DNA methyltransferase inhibitors and histone deacetylase inhibitors have been extensively investigated in CRC. The aim of this review is to provide a brief overview of the preclinical data that represent a proof of principle for the employment of epigenetic agents in CRC with a focus on the advantages of combinatorial therapy over single-drug treatment. We will also critically discuss the results and limitations of initial clinical experiences of epigenetic-based therapy in CRC and summarize ongoing clinical trials. Nevertheless, since recent translational research suggest that epigenetic modulators play a key role in augmenting immunogenicity of the tumor microenvironment and in restoring immune recognition, we will also highlight the recent developments of combinations strategies of immunotherapies and epigenetic therapies in CRC, summarizing preclinical, and clinical data to signify this evolving and promising field for CRC treatment. |
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| Keywords: | Chemosensitization Colorectal cancer DNA methylation DNMTs Epigenetic therapy HDACs Epigenetics Immunotherapy Therapeutics |
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