Epigenetics
Epigenetic biomarkers: key features
l Epigenetic signatures, such as 5mC and 5hmC, are stable and can be mapped/measured using techniques such as oxBS.
l Epigenetic modifications occur early in disease development and may precede genetic changes.
l Epigenetic biomarkers are highly tissue- and disease state-specific, aiding timely intervention with appropriately targeted therapies.
l Highly-sensitive analysis platforms enable epigenetic biomarkers to be effectively identified from clinical samples containing exceptionally low concentrations of DNA (eg LQB samples).
Drug development and personalised approaches to care
Epigenetic changes are intrinsically reversible, making them desirable targets for drug thera- py23,24. Disrupting or inhibiting these modifica- tions may hold the key to effective treatment for a broad range of diseases.
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10 Martino et al. Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance. Genome Biol 2013;14:R42. 11 Heijmans et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA. 2008;4;105(44):17046-9. 12Tobi et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009;1;18(21):4046-53. 13Veenendaal et al. Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine. BJOG 2013;120:548-554. 14Yuan et al. Novel technologies and emerging biomarkers for personalized cancer immunotherapy. Journal for ImmunoTherapy of Cancer 2016;4:3. 15Vaz et al. Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell. 2017;32, 360-376. 16Van Neste et al. Epigenetic risk score improves prostate cancer risk assessment. Prostate. 2017
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techniques such as oxBS, providing an excellent basis for accurate diagnostic and prognostic tools19, particularly in the point of care arena. This is a fast-paced area of development that is showing exceptional promise, leading to the emer- gence of technologies that allow epigenetic signa- tures to be identified from cell, tissue and circulat- ing plasma samples.
Companies have developed proprietary plat- forms that facilitate rapid and precise detection of epigenetic biomarkers from genomic DNA, cell- free DNA (cfDNA) and circulating tumour DNA (ctDNA). Using these highly-sensitive techniques, very low concentrations of cfDNA (<10ng/ml) can be analysed from circulating LQB plasma samples to identify the critical changes within the epigenome that drive disease. Technological advances in this area may also improve the patient experience for people living with diseases such as lung cancer and ovarian can- cer, who currently have to endure highly invasive diagnostic tests (eg pleural fluid sampling, tissue biopsy) that are only able to detect late-stage malignancies20,21. Unsurprisingly, these diseases are associated with extremely poor treatment out- comes. Minimally-invasive LQB techniques and maximally-informative epigenetic biomarkers offer a powerful combination that may enable patients to benefit from the latest diagnostic and prognostic advances using a simple blood test, without undergoing intrusive and uncomfortable clinical procedures.
Robust epigenetic assays that utilise LQB sam- ples and stable biomarkers for disease can be used to stratify patients according to risk and identify individuals who may (or may not) respond to spe- cific treatments as well as those who do not require follow-up chemotherapy (and may subsequently avoid the unpleasant side-effects associated with cytotoxic medicines)22.
Drugs that elicit clinical effects through interac- tions with epigenetic machinery are already in use23. This promising area of research has prompt- ed many pharmaceutical partners to explore agents that target the epigenome in fields such as immuno-oncology and inflammatory disorders. Medicines that modify the activity of epigenetic enzymes and adapter proteins have provided ther- apeutic options for many patients living with con- ditions such as lymphoma or myelodysplastic syn- drome (MDS)23-26. Methylation inhibitors (or hypomethylating agents), such as the DNA methyl- transferase inhibitor (DNMTi) 5-azacytidine, are cytotoxic cancer treatments that have been avail- able for many years23-26. However, these ‘first- generation’ epigenetic drugs can be relatively unstable and associated with unpleasant side- effects. Much research has focused on development of ‘second-generation’ epigenetic medicines that promise a greater degree of selectivity, providing effective management of disease alongside a more acceptable tolerability profile24.
Drugs that are designed to influence epigenetic status provide potential options for novel and more precisely-targeted approaches that cannot be achieved through traditional medicines. Multicomponent treatment regimens that combine epigenetic drugs with other therapeutic com- pounds may allow multiple cellular pathways to be targeted, optimising disease management27. This exciting new area of development includes the emergence of polypharmacology drug delivery sys- tems, in which epigenetic agents are fused with other medicines to form a single multitarget drug that promotes synergistic mechanisms of action between constituent drugs. This approach may offer a more favourable pharmacokinetic profile compared with concomitant administration of individual treatments and could reduce toxicity issues27.
A focus on the future – delivering through partnership
Collaboration and partnership are key to realising the potential of epigenetic research within the clin- ical setting, for the benefit of patients. Commercial partners and academic experts bring unique and valuable insights to these collaborations, with the
Drug Discovery World Fall 2017
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