Progress of epigenetic therapy

1. Progress of epigenetic therapy Melissa Sylvester

2. intro • Moss and Wallrath demonstrated that in some cases reversal of cancer is possible, because of the connection between human disease and epigenetic silencing. • (2) They found a connection through a histone deacetylases inhibitor to cause p53 to silence K27H3 and K9H3, so DMNT will not be transcribed\ (2) However the results are limited in human cancer research because the experiment was conducted on rats. • Use of DNA methyltransferase and histone deacetylases prolonged the life of many patients with myelodysplastic syndrome. • DNA methyltransferase and histone deacetylation activates DNA repair genes, tumor suppressor genes, make cells go through programmed cell death and G0 phase in the cell cycle. (1,2,3,4,6) • (1) Histone deacetylation can do the same action by HDAC attaching to a cyclin dependent kinase inhibitor p21. • The cancer cells going through apoptosis, with the help of tumor suppressor genes, cause patients to live longer. Instead of dying within 4 months as expected, some live three times longer. (3,5,6) Unfortunately, there is success of epigenetic treatment in hematological cancers, like myelodysplastic syndrome. (1)

3. HDAC inhibiting transcription of a gene

4. Target patients Although, all cancers involve cells dividing at an uncontrollable rate, there are selected patients There are two groups of patients with myelodysplastic syndrome: patients with low and high-risk pre leukemia. not one drug helps both groups. (1,3,5,6)

5. Drugs • 2 groups of drugs used: • DNA methyltransferase and histone deacetylases • DNA methyltransferase: (most used) • 5-azacytidine • 5-aza-2-deoxycytidine, • Histone deacetylases • valproic aid • sodium phenyl butyrate • All studies use both inhibitors, but Nachtkamp does not mix the two. (1-6)

6. Effectiveness of drugs • Drugs more effective than 50% if given to patients in low doses for a long period of time • Patient do not get treated then drugs will either no work or have little effect on patient • Also the life span of a patient is prolonged for about 12 months to 24 months than expected to live. (1,2,3,5,6) • Detail: • 5-azacytidine: mean 9 months • 5-aza-2deoxycytidine: 4 months

7. Conclusion: Use of epigenetic drugs helped 55% of myelodysplastic syndrome patients live longer Has stopped some cancerous cells More research needs to be done in epigenetic therapy for all cancers

8. Works Cited 1) Altucci L, Minucci S. Epigenetic therapies in haematological malignancies: Searching for true targets. Eur J Cancer 2009 5;45(7):1137-45 2) Moss TJ, Wallrath LL. Connections between epigenetic gene silencing and human disease. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2007 5/1;618(1–2):163 3) Claus R, Rüter B, Lübbert M. Targets of epigenetic therapy – gene reactivation as a novel approach in MDS treatment. Cancer Treat Rev 2007;33, Supplement 1(0):S47-52 4)Voso MT, D’Alò F, Greco M, Fabiani E, Criscuolo M, Migliara G, Pagano L, Fianchi L, Guidi F, Hohaus S, et al. Epigenetic changes in therapy-related MDS/AML. ChemBiol Interact 2010 3/19;184(1–2):46-9 5)Nachtkamp K, Kündgen A, Strupp C, Giagounidis A, Kobbe G, Gattermann N, Haas R, Germing U. Impact on survival of different treatments for myelodysplastic syndromes (MDS). Leuk Res 2009 8;33(8):1024-8 6)Michael L. Epigenetic therapy for myelodysplastic syndromes has entered center stage. Leuk Res 2009 12;33, Supplement 2(0):S27-8.