Epigenetics: A new frontier in cancer therapy?

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Cancer. What if you could simply “switch” off the gene responsible? The epigenome could hold the answers to painlessly treating the tragic complication.

The advancing tumour manifesting in our body can be eliminated, but cancer treatment still scares us. The rigorous side effects that chemotherapy and radiotherapy can induce on the body lead us to fear fighting death, and instead suffer alone in silence. The true solution may lie in the recently discovered epigenetic therapy.

To delve into the benefits on cancer treatment epigenetics may have, we must explore their general functioning in DNA. Because the strand is extremely long, cells package up their DNA together with proteins known as histones, forming the DNA-protein complex, chromatin. DNA is wrapped around histones forming repeating units called nucleosomes, microscopically examined as “beans on a string”, with the DNA-histone complex resembling the shape of a Malteser. Chromatin is condensed further to form chromosomes and the core of one nucleosome consists of DNA wrapped around a histone octamer, that contains two copies of the major types of histones: H2A, H2B, H3 and H4 .In turn, this carefully organised complex allows cells to regulate which genes are expressed and when, as all of our cells contain the same DNA sequence. Yet all these cells have different structures and functions, why?

This is due to a variation in gene expression, and is the reason why specific cells don’t carry features of others, otherwise we’d end up having our hands as feet, which let’s say the majority of people don’t want! Within each cell, the DNA and even the histones can be tagged with tiny molecules, acting as chemical “switches”, causing some genes to be turned on and some to be turned off. Imagine being in a large room, where only if the light is turned on, you can be guided through it. The same principle applies here, if the light isn’t on for a gene, then it won’t be expressed and will remain in the dark until it appears in our sight through the activation of a switch. These modifications are known as epigenetic modifications, bringing about lasting changes in gene expression.

There are 2 types of epigenetic modification: DNA methylation and histone modification. DNA methylation is when a methyl group is added directly to a cytosine residue that exists in a CpG sequence, and this methylation of “CpG islands” is associated with gene silencing, again resembling the “switch analogy”. In the second type, histone modification, acetyl, methyl, etc. groups are added directly to histone tails hence modifying gene expression through alteration of charges by making the histone less positive, reducing its affinity to DNA.

So, coming back to cancer, which is due to uncontrolled cell division eventually leading to the formation of a tumour. Let’s think about treatment option one: Chemotherapy can be argued to not be ideal as it isn’t in the best interests of many to suffer nausea, fatigue and a plethora of further side effects. Option two: Radiotherapy. From sore skin to stiff joints leading up to fertility issues, the side effects also present a dilemma for researchers striving to treat cancer. But what about treatment three? Epigenetic therapy. Less healthy cells are damaged, meaning less toxic than standard treatments and have fewer side effects, and in my opinion an insight into the future of treating the life-changing disease.

Research has shown that alterations in epigenetic modifications can regulate various cell responses such as its ability to increase in size, apoptosis and invasion. Therefore, epigenetics is said to “play an important role in tumorigenesis” as there are reversible effects on gene silencing and activation via epigenetic enzymes and related proteins. Theoretically, cancer may be caused by methylation of tumour suppressor genes, such as APC and MADR2, frequently deleted or mutated in colon cancers.

Studies indicate that a TET protein that is originally associated with leukaemia can now be linked with prostate and breast cancer. Therefore the key to treating this is to tackle the deficiency formed in this TET protein, as it is associated with breast tumour formation and the inhibition of the methylation of the TIMP family proteins 1 and 2. Research suggests that it is possible that we could resolve this via TET2 proteins as involving this protein into melanoma cells results in a suppression of tumour growth and increased survival rates.

The process of epigenetic drug development begins with a drug screen, which takes place in a laboratory with the cells being assessed for how well they respond to the drug, as well as through epigenetic profiling to see how exactly the epigenome is being affected. Drugs that have the affect of inhibiting cell growth will be cleared to pre-clinical testing, using mice models, eventually leading to clinical studies composed of Phase 1,2,3 testing on samples of humans with increased size of population as the phases are progressed. Careful monitoring of side effects takes place here, and before the drug can be distributed, a last stage of approval administered by regulatory authorities such as the FDA. Some have been approved, such as 5-Azacytadine (Vidaza) to treat the MDS tumour for a rare blood cancer, but this is used in combination with chemotherapies.

Ultimately, cancer is an unpredictable complication, and although there are multitudes of treatments already available for it, the idea of preserving our healthy human cells and making the process of treatment far less agonising is ground-breaking. Epigenetics may still be in its infancy when it comes to cancer treatment, but I see it intrinsic for the future welfare of our patients, both physically and psychologically.


References

1.Cheng Y, He C, Wang M, et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduction and Targeted Therapy. 2019;4(1):1–39. doi:10.1038/s41392-019-0095-0

2.Roberti A, Valdes AF, Torrecillas R, Fraga MF, Fernandez AF. Epigenetics in cancer therapy and nanomedicine. Clinical Epigenetics. 2019;11(1). doi:10.1186/s13148-019-0675-

3.Hatzimichael E, Crook T. Cancer Epigenetics: New Therapies and New Challenges. Journal of Drug Delivery. Published February 26, 2013. Accessed October 23, 2020.

4.Liu Y, Lu Q. Chapter 1 – Introduction to Epigenetics. ScienceDirect. Published January 1, 2015. Accessed October 23, 2020. https://www.sciencedirect.com/science/article/pii/B9780128009574000011

5.Santini, V., Accessed March 2021. Published April 2009. Azacitidine: activity and efficacy as an epigenetic treatment of myelodysplastic syndromes. doi: 10.1586/ehm.09.6.

https://www.sciencedirect.com/science/article/pii/B9780128009574000011

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