Precision Medicine Beyond the Genome

Precision Medicine

April 201832

Beyond the GenomeAs the understanding of the epigenome deepens with successive innovations and applications, collaboration remains key to realising the potential of epigenetic research

Dr Jason Mellad at Cambridge Epigenetix

The epigenome may hold the key to precision medicine, revealing critically important chemical modifications within DNA that alter the structure, function, and regulation of genes. This exciting and rapidly evolving area brings new perspectives to fundamental biological processes underpinning human disease, development, and ageing. Targeting of precise and powerful epigenetic mechanisms may advance personalised medicine beyond the realms of genomics, bringing opportunities for novel therapeutics and diagnostics that will improve patient outcomes and make efficient use of healthcare resources.

Epigenetic modifications within genomes do not alter the underlying sequence of DNA. Instead, precise chemical changes to DNA or RNA nucleotides and histone proteins alter the regulation and function of genes. Epigenetic modifications are inheritable and can be added or removed in response to specific external factors. Patient’s lifestyles (such as smoking and diet), environment, and the stressors that people are exposed to influence the dynamic structure and function of epigenomes, impacting the delicate balance of chemical modifications that are essential to numerous cellular processes.

Informative Diagnostics

Dysregulation of epigenetic pathways can have disastrous consequences; mutations within epigenetic regulators are among the most prevalent across all cancers (1). In addition to cancers, changes within the epigenome are associated with development of a wide range of diseases and health conditions, including neurological and metabolic diseases (2).

Disruption of the epigenome appears to drive the early stages of disease and can precede genetic mutations. Researchers have shown that epigenetic alterations associated with glioblastoma multiforme can be detected in neighbouring non-tumour cells that appear to be genetically ‘normal’ and may drive cancer progression (3). In vitro lung cancer models have also identified epigenetic changes that precede common genetic mutations and are required for tumorigenesis (4). For this reason, chemical modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), which play pivotal roles in essential biological pathways, have also become important biological markers for disease (3,5-8).

These biomarkers are stable, allowing them to be accurately mapped and measured from clinical samples. Epigenetic-based diagnostics provide opportunities for early clinical

intervention before symptom progression has impacted on quality of life when patients are still relatively fit and conditions favour treatment success.

Epigenetic biomarkers may also facilitate improved prognostic prediction and stratification of patients in terms of risk, particularly in therapeutic areas that are associated with a high degree of variability concerning survival (9-11). Further research in glioblastoma and several other cancer types shows that levels of 5hmC are important in the regulation of disease-critical genes, and global changes in hydroxymethylation can be measured to predict patient outcomes (5). Studies have also highlighted that therapeutic resistance may develop as a consequence of chemical changes within the epigenome and resistant phenotypes can develop without genetic changes occurring (1,12). Patients exhibiting these biomarkers will have a greater risk of treatment failure and will need to explore alternative therapeutic options.

Epigenetic Biomarkers: Key Features• Epigenetic biomarkers (such as 5mC and 5hmC) are

stable and deliver high signal intensities, which can be readily mapped and measured using novel techniques such as HMCP

• Epigenetic modifications occur early in disease development, upstream of genetic changes

• The highly specific nature of these biological markers allows precise identification of disease state and tissue type, aiding timely and targeted clinical intervention

• Highly sensitive analysis platforms enable epigenetic biomarkers to be effectively identified from clinical samples containing exceptionally low concentrations of DNA (eg LQB samples)

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Recent innovations enable accurate quantification and mapping of critical epigenetic marks or signatures, which cannot be identified and measured using traditional genetic research techniques. Technologies that leverage this approach, such as HMCP (5-hmC profiling) platform, have the potential to revolutionise patient-centred diagnostics. Used in combination with techniques such as liquid biopsy (LQB), these platforms provide swift and accurate analysis of clinical samples from cells, tissue, and circulating plasma to facilitate early detection of disease and epigenetic risk factors (1,13).

Technological advances in this area may improve the patient experience for people living with diseases such as lung cancer and ovarian cancer who currently have to endure highly invasive diagnostic tests (eg pleural fluid sampling and tissue biopsy) that are only able to detect late-stage malignancies (14-15). These diseases generally have extremely poor treatment outcomes. The powerful combination of minimally invasive LQB techniques and maximally informative epigenetic biomarkers may allow patients to benefit from the latest diagnostic and prognostic advances using a simple blood test, without undergoing intrusive and uncomfortable clinical procedures.

New Therapeutics

Epigenetic changes are intrinsically reversible, making them desirable targets for leading-edge drug therapy (2,16). Disrupting or inhibiting epigenetic machinery brings new possibilities for effective treatment of a broad range of diseases. The pharmaceutical industry has embraced this opportunity, exploring epigenetic-based medicines in fields such as immuno-oncology and inflammatory disorders.

Drugs that elicit clinical effects via the epigenome are already in use; cytotoxic cancer treatments such as azacytidine (a hypomethylating agent) have been used for the treatment of conditions such as acute myeloid leukaemia (AML) for many years (1-2). 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 profile (17).

Drugs that are designed to influence epigenetic status provides potential options for true precision medicine – targeting mechanisms that cannot be reached through traditional medicines. Multicomponent treatment regimens and combination therapies that administer epigenetic drugs alongside other therapeutic compounds may allow multiple cellular pathways to be targeted, optimising disease management (1,17). This exciting new area of development includes the emergence of polypharmacology drug delivery systems, in which epigenetic agents are fused with other medicines to form a single multi-target drug that promotes synergistic mechanisms of action between constituent

drugs. Polypharmacological approaches may offer a more favourable pharmacokinetic profile, compared with concomitant administration of individual treatments, and could reduce toxicity issues (18).

Delivering on the Promise

Accurate and robust biomarkers are at the heart of precision medicine. Well-characterised epigenetic signatures have the ability to drive highly focused and targeted approaches to early stage diagnostics and treatment of complex diseases. Additionally, the evolving knowledge concerning epigenetic mechanisms has inspired a new generation of potent and effective therapeutics that may offer improved tolerability (1,18).

Collaboration is critical in realising the potential of epigenetic research within the clinical setting for the benefit of patients. Commercial partners and academic experts bring unique and valuable insights to these collaborations, with the necessary investment to package and deliver new technologies appropriately. Companies are working alongside academic and clinical partners to drive fresh innovations and access well-defined sample sets that will improve identification and management of disease.

As understanding of the epigenome continues to deepen, the opportunities for innovation and application of this knowledge in the clinical setting are expanding tremendously. These advances look set to transform the approach to the management of human health and well-being, enabling ongoing monitoring of the epigenome and opportunities to implement clinical interventions early in disease development or adapt lifestyles appropriately to avoid health issues.

References1. Dawson MA, The cancer epigenome: Concepts,

challenges, and therapeutic opportunities, Science 355(6,330): pp1,147-52, 2017

2. Heerboth S et al, Use of epigenetic drugs in disease: An overview, Genet Epigenet 6: pp9-19, 2014

3. Raiber E et al, Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma, Genomic Medicine 2(6): 2017

4. Vaz M et al, Chronic cigarette smoke-induced epigenomic changes precede sensitization of bronchial epithelial cells to single-step transformation by KRAS mutations, Cancer Cell 32(3): pp360-76, 2017

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5. Johnson KC et al, 5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients, Nat Commun 7: p13,177, 2016

6. López V et al, The role of 5-hydroxymethylcytosine in development, aging and age-related diseases, Ageing Res Rev 37: pp28-38, 2017

7. Tahiliani M et al, Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1, Science 324 (5,929): pp930-5, 2009

8. Scourzic L et al, TET proteins and the control of cytosine demethylation in cancer, Genome Med 7(1): p9, 2015

9. Yuan J et al, Novel technologies and emerging biomarkers for personalized cancer immunotherapy, J Immunother Cancer 4: p3, 2016

10. Van Neste L et al, Epigenetic risk score improves prostate cancer risk assessment, Prostate 77(12): pp1,259-64, 2017

11. Koschmieder S and Vetrie D, Epigenetic dysregulation in chronic myeloid leukaemia: A myriad of mechanisms and therapeutic options, Semin Cancer Biol: 2017

12. Fong CY et al, BET inhibitor resistance emerges from leukaemia stem cells, Nature, 525(7,570): pp538-42, 2015

13. Gyparaki MT et al, DNA methylation biomarkers as diagnostic and prognostic tools in colorectal cancer, J Mol Med (Berl) 91(11): pp1,249-56, 2013

Dr Jason Mellad is the CEO at Cambridge Epigenetix, which aims to change the way medicine is practised by reducing several routine and important diagnostic screening tests to a simple blood draw using the power of 5hmC epigenetic modification. Jason

has a BSc in molecular biology and chemistry from Tulane University, US, and was a Marshall Scholar at the University of Cambridge, UK, where he completed a PhD in medicine. Email: [email protected]

About the author

14. Tomasetti M et al, Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy, Lung Cancer 107: pp65-71, 2017

15. Giannopoulou L et al, Liquid biopsy in ovarian cancer: Recent advances on circulating tumor cells and circulating tumor DNA, Clin Chem Lab Med 56(2): pp186-97, 2018

16. Qi Y et al, HEDD: The human epigenetic drug database, Database: 2016

17. Altucci L and Rots MG, Epigenetic drugs: From chemistry via biology to medicine and back, Clin Epigenetics 8: p56, 2016

18. de Lera AR and Ganesan A, Epigenetic polypharmacology: From combination therapy to multitargeted drugs, Clin Epigenetics 8: p105, 2016