Review
BibTex RIS Cite

Current Epigenetic Treatments

Year 2024, Volume: 3 Issue: 3, 111 - 118, 01.10.2024
https://doi.org/10.59518/farabimedj.1542765

Abstract

The epigenetic mechanisms are defined as alterations in gene expression levels through histone modifications, DNA methylations and non-coding RNAs without any change in DNA sequence. Studies conducted at the molecular level have shown that epigenetic regulations are key players in the pathogenesis of many diseases, and effective biomarkers have been identified in the diagnosis and prognosis of some diseases. While the research of the identified biomarkers in clinical trials carry on, some epigenetic treatment tools are started to be used in treatment with FDA approval. Histone deacetylase inhibitors, DNA methyl transferase inhibitors and non-coding RNAs are used for therapeutic purposes in the pathogenesis of many diseases, especially cancer. Although it took time for epigenetic therapies to be approved, their effectiveness has been shown and is now applied in the clinic as a single or combined therapy. For this reason, it is important to elucidate and investigate epigenetic targets and their functions and cross-talk between epigenetic mediator, modulator and regulator proteins. This review will summarise the epigenetic therapies that are used in routine clinical practice, have received FDA approval, and are frequently used in clinical trials.

References

  • 1. Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009;324(5929):929-930.
  • Zhang Y, Zhou C. Formation and biological consequences of 5-Formylcytosine in genomic DNA. DNA Repair (Amst). 2019;81:102649.
  • Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17(10):630-641.
  • Smith ZD, Hetzel S, Meissner A. DNA methylation in mammalian development and disease. Nat Rev Genet. Published online August 12, 2024. doi:10.1038/s41576-024-00760-8.
  • Rimoldi M, Wang N, Zhang J, et al. DNA methylation patterns of transcription factor binding regions characterize their functional and evolutionary contexts. Genome Biol. 2024;25(1):146.
  • Park JW, Han JW. Targeting epigenetics for cancer therapy. Arch Pharm Res. 2019;42(2):159-170.
  • Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. The lancet oncology. 2009;10(3):223-232.
  • Hu C, Liu X, Zeng Y, Liu J, Wu F. DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application. Clin Epigenetics. 2021;13(1):166.
  • Papadatos-Pastos D, Yuan W, Pal A, et al. Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors. J Immunother Cancer. Jun 2022;10(6).
  • Nie J, Wang C, Liu Y, et al. Addition of Low-Dose Decitabine to Anti-PD-1 Antibody Camrelizumab in Relapsed/Refractory Classical Hodgkin Lymphoma. J Clin Oncol. 2019;37(17):1479-1489.
  • Von Hoff DD, Rasco DW, Heath EI, et al. Phase I Study of CC-486 Alone and in Combination with Carboplatin or nab-Paclitaxel in Patients with Relapsed or Refractory Solid Tumors. Clin Cancer Res. 2018;24(17):4072-4080.
  • Connolly RM, Li H, Jankowitz RC, et al. Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study. Clin Cancer Res. 2017;23(11):2691-2701.
  • Liang G, Weisenberger DJ. DNA methylation aberrancies as a guide for surveillance and treatment of human cancers. Epigenetics. 2017;12(6):416-432.
  • Fu S, Hu W, Iyer R, et al. Phase 1b‐2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum‐resistant or platinum‐refractory epithelial ovarian cancer. Cancer. 2011;117(8):1661-1669.
  • Laranjeira ABA, Hollingshead MG, Nguyen D, Kinders RJ, Doroshow JH, Yang SX. DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors. Sci Rep. 2023;13(1):5964.
  • Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41-45.
  • Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693-705.
  • Fullgrabe J, Kavanagh E, Joseph B. Histone onco-modifications. Oncogene. 2011;30(31):3391-3403.
  • Bajbouj K, Al-Ali A, Ramakrishnan RK, Saber-Ayad M, Hamid Q. Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets. Int J Mol Sci. 2021;22(21):11701. doi:10.3390/ijms222111701
  • Fraga MF, Ballestar E, Villar-Garea A, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature genetics. 2005;37(4):391-400.
  • Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nature reviews Drug discovery. 2014;13(9):673-691.
  • Audia JE, Campbell RM. Histone Modifications and Cancer. Cold Spring Harb Perspect Biol. 2016;8(4):a019521.
  • San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195-1206.
  • Shanmugam G, Rakshit S, Sarkar K. HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases. Transl Oncol. 2022;16:101312.
  • Chen Y, Ren B, Yang J, et al. The role of histone methylation in the development of digestive cancers: a potential direction for cancer management. Signal Transduct Target Ther. 2020;5(1):143.
  • Colon-Bolea P, Crespo P. Lysine methylation in cancer: SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK pathway. Bioessays. 2014;36(12):1162-1169.
  • Lima-Fernandes E, Murison A, da Silva Medina T, et al. Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells. Nat Commun. 2019;10(1):1436.
  • Zhang C, Zhang B. RNA therapeutics: updates and future potential. Sci China Life Sci. 2023;66(1):12-30.
  • Kristen AV, Ajroud-Driss S, Conceicao I, Gorevic P, Kyriakides T, Obici L. Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis. Neurodegener Dis Manag. 2019;9(1):5-23.
  • Debacker AJ, Voutila J, Catley M, Blakey D, Habib N. Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug. Mol Ther. 2020;28(8):1759-1771.
  • Balwani M, Sardh E, Ventura P, et al. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020;382(24):2289-2301.
  • Garrelfs SF, Frishberg Y, Hulton SA, et al. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N Engl J Med. 2021;384(13):1216-1226.
  • Scott LJ, Keam SJ. Lumasiran: First Approval. Drugs. 2021;81(2):277-282.
  • Lamb YN. Inclisiran: First Approval. Drugs. 2021;81(3):389-395.
  • Machin N, Ragni MV. An investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B. J Blood Med. 2018;9:135-140.
  • Kletzmayr A, Ivarsson ME, Leroux JC. Investigational Therapies for Primary Hyperoxaluria. Bioconjug Chem. 2020;31(7):1696-1707.
  • Gallagher KM, O'Neill S, Harrison EM, Ross JA, Wigmore SJ, Hughes J. Recent early clinical drug development for acute kidney injury. Expert Opin Investig Drugs. 2017;26(2):141-154.
  • Moreno-Montanes J, Bleau AM, Jimenez AI. Tivanisiran, a novel siRNA for the treatment of dry eye disease. Expert Opin Investig Drugs. 2018;27(4):421-426.
  • Habtemariam BA, Karsten V, Attarwala H, et al. Single-Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N-acetylgalactosamine-Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects. Clin Pharmacol Ther. 2021;109(2):372-382.
  • van Zandwijk N, Pavlakis N, Kao SC, et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol. 2017;18(10):1386-1396.
  • Foss FM, Querfeld C, Kim YH, et al. Ph 1 study of MRG-106, an inhibitor of miR-155, in CTCL: Journal of Clinical Oncology. 2018;36(15):2511-2511. doi:10.1200/JCO.2018.36.15_suppl.2511
  • Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685-1694.
  • Kara G, Calin GA, Ozpolat B. RNAi-based therapeutics and tumor targeted delivery in cancer. Adv Drug Deliv Rev. 2022;182:114113.
  • Griazeva ED, Fedoseeva DM, Radion EI, et al. Current Approaches to Epigenetic Therapy. Epigenomes. 2023;7(4):23.. doi:10.3390/epigenomes7040023
  • Winkle M, El-Daly SM, Fabbri M, Calin GA. Noncoding RNA therapeutics - challenges and potential solutions. Nat Rev Drug Discov. 2021;20(8):629-651.
  • Rabaan AA, AlSaihati H, Bukhamsin R, et al. Application of CRISPR/Cas9 Technology in Cancer Treatment: A Future Direction. Curr Oncol. 2023;30(2):1954-1976.
  • Sharma G, Sharma AR, Bhattacharya M, Lee SS, Chakraborty C. CRISPR-Cas9: A Preclinical and Clinical Perspective for the Treatment of Human Diseases. Mol Ther. 2021;29(2):571-586.
  • Segal M, Slack FJ. Challenges identifying efficacious miRNA therapeutics for cancer. Expert Opin Drug Discov. 2020;15(9):987-992.

Güncel Epigenetik Tedaviler

Year 2024, Volume: 3 Issue: 3, 111 - 118, 01.10.2024
https://doi.org/10.59518/farabimedj.1542765

Abstract

Epigenetik mekanizmalar, histon modifikasyonları, DNA metilasyonları ve kodlanmayan RNA’lar aracılığı ile DNA dizisinde herhangi bir değişiklik göstermeksizin, gen ifade düzeylerinin değişmesi olarak tanımlanmaktadır. Yapılan araştırmalar, epigenetik değişikliklerin birçok hastalığın patogenezinde etkin olduğunu göstermiş, bazı hastalıkların tanı ve prognozunda etkili biyobelirteçler tespit edilmiştir. Belirlenen biyobelirteçlerin hedeflenerek klinik çalışmalarda araştırılması devam ederken, kimi epigenetik tedavi araçları FDA onayı ile tedavide kullanılmaktadır. Histon deasetilaz inhibitörleri, DNA metil transferaz inhibitörleri ve kodlanmayan RNA’lar başta kanser olmak üzere tekli veya kombine olarak birçok hastalığın patogenezinde tedavi amaçlı kullanılmaktadır. Her ne kadar epigenetik tedavilerin kabul görmesi zaman almış olsa da, etkinliği kanıtlanmıştır ve günümüzde tek veya kombine terapi olarak klinikte uygulanmaktadır. Bu sebeple epigenetik mekanizmaların aydınlatılarak hedeflerinin ve düzenleyicilerinin belirlenmesi ve bu hedeflerin işlevlerinin araştırılması önem arz etmektedir. Bu derlemede rutin klinik uygulamada kullanılan, FDA onayı almış ve klinik araştırmalarda sıklıkla kullanılan epigenetik terapiler özetlenecektir.

References

  • 1. Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009;324(5929):929-930.
  • Zhang Y, Zhou C. Formation and biological consequences of 5-Formylcytosine in genomic DNA. DNA Repair (Amst). 2019;81:102649.
  • Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17(10):630-641.
  • Smith ZD, Hetzel S, Meissner A. DNA methylation in mammalian development and disease. Nat Rev Genet. Published online August 12, 2024. doi:10.1038/s41576-024-00760-8.
  • Rimoldi M, Wang N, Zhang J, et al. DNA methylation patterns of transcription factor binding regions characterize their functional and evolutionary contexts. Genome Biol. 2024;25(1):146.
  • Park JW, Han JW. Targeting epigenetics for cancer therapy. Arch Pharm Res. 2019;42(2):159-170.
  • Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. The lancet oncology. 2009;10(3):223-232.
  • Hu C, Liu X, Zeng Y, Liu J, Wu F. DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application. Clin Epigenetics. 2021;13(1):166.
  • Papadatos-Pastos D, Yuan W, Pal A, et al. Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors. J Immunother Cancer. Jun 2022;10(6).
  • Nie J, Wang C, Liu Y, et al. Addition of Low-Dose Decitabine to Anti-PD-1 Antibody Camrelizumab in Relapsed/Refractory Classical Hodgkin Lymphoma. J Clin Oncol. 2019;37(17):1479-1489.
  • Von Hoff DD, Rasco DW, Heath EI, et al. Phase I Study of CC-486 Alone and in Combination with Carboplatin or nab-Paclitaxel in Patients with Relapsed or Refractory Solid Tumors. Clin Cancer Res. 2018;24(17):4072-4080.
  • Connolly RM, Li H, Jankowitz RC, et al. Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study. Clin Cancer Res. 2017;23(11):2691-2701.
  • Liang G, Weisenberger DJ. DNA methylation aberrancies as a guide for surveillance and treatment of human cancers. Epigenetics. 2017;12(6):416-432.
  • Fu S, Hu W, Iyer R, et al. Phase 1b‐2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum‐resistant or platinum‐refractory epithelial ovarian cancer. Cancer. 2011;117(8):1661-1669.
  • Laranjeira ABA, Hollingshead MG, Nguyen D, Kinders RJ, Doroshow JH, Yang SX. DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors. Sci Rep. 2023;13(1):5964.
  • Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41-45.
  • Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693-705.
  • Fullgrabe J, Kavanagh E, Joseph B. Histone onco-modifications. Oncogene. 2011;30(31):3391-3403.
  • Bajbouj K, Al-Ali A, Ramakrishnan RK, Saber-Ayad M, Hamid Q. Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets. Int J Mol Sci. 2021;22(21):11701. doi:10.3390/ijms222111701
  • Fraga MF, Ballestar E, Villar-Garea A, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature genetics. 2005;37(4):391-400.
  • Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nature reviews Drug discovery. 2014;13(9):673-691.
  • Audia JE, Campbell RM. Histone Modifications and Cancer. Cold Spring Harb Perspect Biol. 2016;8(4):a019521.
  • San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195-1206.
  • Shanmugam G, Rakshit S, Sarkar K. HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases. Transl Oncol. 2022;16:101312.
  • Chen Y, Ren B, Yang J, et al. The role of histone methylation in the development of digestive cancers: a potential direction for cancer management. Signal Transduct Target Ther. 2020;5(1):143.
  • Colon-Bolea P, Crespo P. Lysine methylation in cancer: SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK pathway. Bioessays. 2014;36(12):1162-1169.
  • Lima-Fernandes E, Murison A, da Silva Medina T, et al. Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells. Nat Commun. 2019;10(1):1436.
  • Zhang C, Zhang B. RNA therapeutics: updates and future potential. Sci China Life Sci. 2023;66(1):12-30.
  • Kristen AV, Ajroud-Driss S, Conceicao I, Gorevic P, Kyriakides T, Obici L. Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis. Neurodegener Dis Manag. 2019;9(1):5-23.
  • Debacker AJ, Voutila J, Catley M, Blakey D, Habib N. Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug. Mol Ther. 2020;28(8):1759-1771.
  • Balwani M, Sardh E, Ventura P, et al. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020;382(24):2289-2301.
  • Garrelfs SF, Frishberg Y, Hulton SA, et al. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N Engl J Med. 2021;384(13):1216-1226.
  • Scott LJ, Keam SJ. Lumasiran: First Approval. Drugs. 2021;81(2):277-282.
  • Lamb YN. Inclisiran: First Approval. Drugs. 2021;81(3):389-395.
  • Machin N, Ragni MV. An investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B. J Blood Med. 2018;9:135-140.
  • Kletzmayr A, Ivarsson ME, Leroux JC. Investigational Therapies for Primary Hyperoxaluria. Bioconjug Chem. 2020;31(7):1696-1707.
  • Gallagher KM, O'Neill S, Harrison EM, Ross JA, Wigmore SJ, Hughes J. Recent early clinical drug development for acute kidney injury. Expert Opin Investig Drugs. 2017;26(2):141-154.
  • Moreno-Montanes J, Bleau AM, Jimenez AI. Tivanisiran, a novel siRNA for the treatment of dry eye disease. Expert Opin Investig Drugs. 2018;27(4):421-426.
  • Habtemariam BA, Karsten V, Attarwala H, et al. Single-Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N-acetylgalactosamine-Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects. Clin Pharmacol Ther. 2021;109(2):372-382.
  • van Zandwijk N, Pavlakis N, Kao SC, et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol. 2017;18(10):1386-1396.
  • Foss FM, Querfeld C, Kim YH, et al. Ph 1 study of MRG-106, an inhibitor of miR-155, in CTCL: Journal of Clinical Oncology. 2018;36(15):2511-2511. doi:10.1200/JCO.2018.36.15_suppl.2511
  • Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685-1694.
  • Kara G, Calin GA, Ozpolat B. RNAi-based therapeutics and tumor targeted delivery in cancer. Adv Drug Deliv Rev. 2022;182:114113.
  • Griazeva ED, Fedoseeva DM, Radion EI, et al. Current Approaches to Epigenetic Therapy. Epigenomes. 2023;7(4):23.. doi:10.3390/epigenomes7040023
  • Winkle M, El-Daly SM, Fabbri M, Calin GA. Noncoding RNA therapeutics - challenges and potential solutions. Nat Rev Drug Discov. 2021;20(8):629-651.
  • Rabaan AA, AlSaihati H, Bukhamsin R, et al. Application of CRISPR/Cas9 Technology in Cancer Treatment: A Future Direction. Curr Oncol. 2023;30(2):1954-1976.
  • Sharma G, Sharma AR, Bhattacharya M, Lee SS, Chakraborty C. CRISPR-Cas9: A Preclinical and Clinical Perspective for the Treatment of Human Diseases. Mol Ther. 2021;29(2):571-586.
  • Segal M, Slack FJ. Challenges identifying efficacious miRNA therapeutics for cancer. Expert Opin Drug Discov. 2020;15(9):987-992.
There are 48 citations in total.

Details

Primary Language Turkish
Subjects Medical Genetics (Excl. Cancer Genetics)
Journal Section Reviews
Authors

Didem Seven 0000-0003-3406-5905

Publication Date October 1, 2024
Submission Date September 3, 2024
Acceptance Date September 30, 2024
Published in Issue Year 2024 Volume: 3 Issue: 3

Cite

AMA Seven D. Güncel Epigenetik Tedaviler. Farabi Med J. October 2024;3(3):111-118. doi:10.59518/farabimedj.1542765

*The articles to be sent to the journal should be prepared according to the sample files given below. Manuscripts not prepared in accordance with the journal format will be returned to the Author(s).

1. ORIGİNAL ARTİCLE TEMPLATE/ÖZGÜN MAKALE ŞABLONU

2. CASE REPORT TEMPLATE/OLGU SUNUMU ŞABLONU

3. REVİEW TEMPLATE /DERLEME ŞABLONU

4. TITLE PAGE/BAŞLIK SAYFASI

5. COPYRİGHT TRANSFER FORM/TELİF HAKKI DEVİR FORMU

6. COVER LETTER/KAPAK YAZISI

**International Medical Journals Editorial Board (ICMJE) directive