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06.01.2025 | Epigenetik | Fokus

Epigenetische Therapien in der Krebsbehandlung: Chancen und Herausforderungen

verfasst von: Prof. Dr. med. Elisabeth Hessmann, Prof. Dr. med. Günter Schneider

Erschienen in: Forum

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Zusammenfassung

Epigenetische Therapien bieten ein vielversprechendes neues Behandlungskonzept für verschiedene Krankheiten, insbesondere Krebs. Indem sie die epigenetischen Veränderungen umkehren, die zur Entstehung von Krankheiten beitragen, können diese Therapien die Genexpression gezielt modulieren und das Wachstum von Tumorzellen hemmen. Anhand von EZH2-Inhibitoren („enhancer of zeste homolog 2“) diskutieren wir aktuelle Entwicklungen in der epigenetischen Therapie und zeigen Wege auf, das volle Potenzial epigenetischer Therapeutika auszuschöpfen.
Literatur
1.
2.
Zurück zum Zitat Hessmann E et al (2017) Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon? Gut 66(1):168–179PubMedCrossRef Hessmann E et al (2017) Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon? Gut 66(1):168–179PubMedCrossRef
3.
Zurück zum Zitat Chen NM et al (2017) Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity. Gastroenterology 152(6):1507–1520PubMedCrossRef Chen NM et al (2017) Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity. Gastroenterology 152(6):1507–1520PubMedCrossRef
4.
Zurück zum Zitat Kitamura T (2019) Epigenetic abnormalities and therapies for hematological malignancies. Int J Hematol 110(2):147–149PubMedCrossRef Kitamura T (2019) Epigenetic abnormalities and therapies for hematological malignancies. Int J Hematol 110(2):147–149PubMedCrossRef
5.
Zurück zum Zitat Rossi A et al (2024) Progresses and Pitfalls of Epigenetics in Solid Tumors Clinical Trials. Int J Mol Sci 25(21) Rossi A et al (2024) Progresses and Pitfalls of Epigenetics in Solid Tumors Clinical Trials. Int J Mol Sci 25(21)
6.
7.
Zurück zum Zitat Fili C et al (2019) Efficacy and toxicity of Decitabine in patients with acute myeloid leukemia (AML): A multicenter real-world experience. Leuk Res 76:33–38PubMedCrossRef Fili C et al (2019) Efficacy and toxicity of Decitabine in patients with acute myeloid leukemia (AML): A multicenter real-world experience. Leuk Res 76:33–38PubMedCrossRef
8.
Zurück zum Zitat Gounder M et al (2020) Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol 21(11):1423–1432PubMedCrossRef Gounder M et al (2020) Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol 21(11):1423–1432PubMedCrossRef
9.
Zurück zum Zitat Versemann L, Hessmann E, Ulisse M (2022) Epigenetic Therapeutic Strategies to Target Molecular and Cellular Heterogeneity in Pancreatic Cancer. Visc Med 38(1):11–19PubMedCrossRef Versemann L, Hessmann E, Ulisse M (2022) Epigenetic Therapeutic Strategies to Target Molecular and Cellular Heterogeneity in Pancreatic Cancer. Visc Med 38(1):11–19PubMedCrossRef
10.
Zurück zum Zitat Versemann L et al (2022) TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer. Cancers (basel) 14(14) Versemann L et al (2022) TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer. Cancers (basel) 14(14)
11.
Zurück zum Zitat Cheng Y et al (2019) Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther 4:62PubMedPubMedCentralCrossRef Cheng Y et al (2019) Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther 4:62PubMedPubMedCentralCrossRef
12.
13.
Zurück zum Zitat Chen YH, Hung MC, Li LY (2012) EZH2: a pivotal regulator in controlling cell differentiation. Am J Transl Res 4(4):364–375PubMedPubMedCentral Chen YH, Hung MC, Li LY (2012) EZH2: a pivotal regulator in controlling cell differentiation. Am J Transl Res 4(4):364–375PubMedPubMedCentral
15.
Zurück zum Zitat McCabe MT et al (2012) Mutation of A677 in histone methyltransferase EZH2 in human B‑cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A 109(8):2989–2994PubMedPubMedCentralCrossRef McCabe MT et al (2012) Mutation of A677 in histone methyltransferase EZH2 in human B‑cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A 109(8):2989–2994PubMedPubMedCentralCrossRef
16.
Zurück zum Zitat Morin RD et al (2010) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B‑cell lymphomas of germinal-center origin. Nat Genet 42(2):181–185PubMedPubMedCentralCrossRef Morin RD et al (2010) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B‑cell lymphomas of germinal-center origin. Nat Genet 42(2):181–185PubMedPubMedCentralCrossRef
17.
Zurück zum Zitat Bachmann IM et al (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24(2):268–273PubMedCrossRef Bachmann IM et al (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24(2):268–273PubMedCrossRef
18.
Zurück zum Zitat Behrens C et al (2013) EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma. Clin Cancer Res 19(23):6556–6565PubMedPubMedCentralCrossRef Behrens C et al (2013) EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma. Clin Cancer Res 19(23):6556–6565PubMedPubMedCentralCrossRef
19.
Zurück zum Zitat Bracken AP et al (2006) Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 20(9):1123–1136PubMedPubMedCentralCrossRef Bracken AP et al (2006) Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 20(9):1123–1136PubMedPubMedCentralCrossRef
20.
Zurück zum Zitat Fujii S et al (2011) MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene 30(39):4118–4128PubMedCrossRef Fujii S et al (2011) MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene 30(39):4118–4128PubMedCrossRef
21.
Zurück zum Zitat Jones BA, Varambally S, Histone Methyltransferase RCA (2018) EZH2: A Therapeutic Target for Ovarian Cancer. Mol Cancer Ther 17(3):591–602PubMedPubMedCentralCrossRef Jones BA, Varambally S, Histone Methyltransferase RCA (2018) EZH2: A Therapeutic Target for Ovarian Cancer. Mol Cancer Ther 17(3):591–602PubMedPubMedCentralCrossRef
22.
Zurück zum Zitat Kleer CG et al (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A 100(20):11606–11611PubMedPubMedCentralCrossRef Kleer CG et al (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A 100(20):11606–11611PubMedPubMedCentralCrossRef
24.
Zurück zum Zitat Ougolkov AV, Bilim VN, Billadeau DD (2008) Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin Cancer Res 14(21):6790–6796PubMedPubMedCentralCrossRef Ougolkov AV, Bilim VN, Billadeau DD (2008) Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin Cancer Res 14(21):6790–6796PubMedPubMedCentralCrossRef
25.
Zurück zum Zitat Patil S et al (2020) EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6. Cancer Res 80(21):4620–4632PubMedCrossRef Patil S et al (2020) EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6. Cancer Res 80(21):4620–4632PubMedCrossRef
26.
Zurück zum Zitat Varambally S et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419(6907):624–629PubMedCrossRef Varambally S et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419(6907):624–629PubMedCrossRef
27.
28.
Zurück zum Zitat Weikert S et al (2005) Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med 16(2):349–353PubMed Weikert S et al (2005) Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med 16(2):349–353PubMed
29.
Zurück zum Zitat Kaur P, Shankar E, Gupta S (2024) EZH2-mediated development of therapeutic resistance in cancer. Cancer Lett 586:216706PubMedCrossRef Kaur P, Shankar E, Gupta S (2024) EZH2-mediated development of therapeutic resistance in cancer. Cancer Lett 586:216706PubMedCrossRef
30.
Zurück zum Zitat Gan L et al (2018) Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential. Biomark Res 6:10PubMedPubMedCentralCrossRef Gan L et al (2018) Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential. Biomark Res 6:10PubMedPubMedCentralCrossRef
31.
Zurück zum Zitat Pasini D, Di Croce L (2016) Emerging roles for Polycomb proteins in cancer. Curr Opin Genet Dev 36:50–58PubMedCrossRef Pasini D, Di Croce L (2016) Emerging roles for Polycomb proteins in cancer. Curr Opin Genet Dev 36:50–58PubMedCrossRef
32.
Zurück zum Zitat Yamagishi M, Uchimaru K (2017) Targeting EZH2 in cancer therapy. Curr Opin Oncol 29(5):375–381PubMedCrossRef Yamagishi M, Uchimaru K (2017) Targeting EZH2 in cancer therapy. Curr Opin Oncol 29(5):375–381PubMedCrossRef
33.
Zurück zum Zitat Ma A et al (2020) Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol 16(2):214–222PubMedCrossRef Ma A et al (2020) Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol 16(2):214–222PubMedCrossRef
34.
Zurück zum Zitat Knutson SK et al (2014) Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther 13(4):842–854PubMedCrossRef Knutson SK et al (2014) Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther 13(4):842–854PubMedCrossRef
35.
Zurück zum Zitat Knutson SK et al (2012) A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 8(11):890–896PubMedCrossRef Knutson SK et al (2012) A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 8(11):890–896PubMedCrossRef
36.
Zurück zum Zitat McCabe MT et al (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492(7427):108–112PubMedCrossRef McCabe MT et al (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492(7427):108–112PubMedCrossRef
37.
Zurück zum Zitat Morschhauser F et al (2020) Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 21(11):1433–1442PubMedPubMedCentralCrossRef Morschhauser F et al (2020) Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 21(11):1433–1442PubMedPubMedCentralCrossRef
38.
Zurück zum Zitat Lee ST et al (2011) Context-specific regulation of NF-kappaB target gene expression by EZH2 in breast cancers. Mol Cell 43(5):798–810PubMedCrossRef Lee ST et al (2011) Context-specific regulation of NF-kappaB target gene expression by EZH2 in breast cancers. Mol Cell 43(5):798–810PubMedCrossRef
39.
Zurück zum Zitat Shi B et al (2007) Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol 27(14):5105–5119PubMedPubMedCentralCrossRef Shi B et al (2007) Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol 27(14):5105–5119PubMedPubMedCentralCrossRef
42.
Zurück zum Zitat Kim E et al (2013) Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23(6):839–852PubMedPubMedCentralCrossRef Kim E et al (2013) Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23(6):839–852PubMedPubMedCentralCrossRef
43.
Zurück zum Zitat Gunawan M et al (2015) The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nat Immunol 16(5):505–516PubMedCrossRef Gunawan M et al (2015) The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nat Immunol 16(5):505–516PubMedCrossRef
44.
Zurück zum Zitat Patil S et al (2021) Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer. Cells 10(12) Patil S et al (2021) Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer. Cells 10(12)
45.
Zurück zum Zitat Romanelli A et al (2020) Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells. ACS Med Chem Lett 11(5):977–983PubMedPubMedCentralCrossRef Romanelli A et al (2020) Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells. ACS Med Chem Lett 11(5):977–983PubMedPubMedCentralCrossRef
46.
Zurück zum Zitat Takashina T et al (2016) Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells. Cancer Sci 107(7):955–962PubMedPubMedCentralCrossRef Takashina T et al (2016) Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells. Cancer Sci 107(7):955–962PubMedPubMedCentralCrossRef
47.
Zurück zum Zitat Zhang L et al (2022) DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma. Cancer Lett 548:215899PubMedPubMedCentralCrossRef Zhang L et al (2022) DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma. Cancer Lett 548:215899PubMedPubMedCentralCrossRef
48.
Zurück zum Zitat Li C et al (2021) Finding an easy way to harmonize: a review of advances in clinical research and combination strategies of EZH2 inhibitors. Clin Epigenetics 13(1):62PubMedPubMedCentralCrossRef Li C et al (2021) Finding an easy way to harmonize: a review of advances in clinical research and combination strategies of EZH2 inhibitors. Clin Epigenetics 13(1):62PubMedPubMedCentralCrossRef
49.
Zurück zum Zitat Yamaguchi H et al (2018) EZH2 contributes to the response to PARP inhibitors through its PARP-mediated poly-ADP ribosylation in breast cancer. Oncogene 37(2):208–217PubMedCrossRef Yamaguchi H et al (2018) EZH2 contributes to the response to PARP inhibitors through its PARP-mediated poly-ADP ribosylation in breast cancer. Oncogene 37(2):208–217PubMedCrossRef
50.
Zurück zum Zitat Xu L et al (2019) Pharmacological inhibition of EZH2 combined with DNA-damaging agents interferes with the DNA damage response in MM cells. Mol Med Rep 19(5):4249–4255PubMedPubMedCentral Xu L et al (2019) Pharmacological inhibition of EZH2 combined with DNA-damaging agents interferes with the DNA damage response in MM cells. Mol Med Rep 19(5):4249–4255PubMedPubMedCentral
51.
Zurück zum Zitat Tumes DJ et al (2013) The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity 39(5):819–832PubMedCrossRef Tumes DJ et al (2013) The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity 39(5):819–832PubMedCrossRef
53.
Zurück zum Zitat Chen X et al (2020) Epigenetic strategies synergize with PD-L1/PD‑1 targeted cancer immunotherapies to enhance antitumor responses. Acta Pharm Sin B 10(5):723–733PubMedCrossRef Chen X et al (2020) Epigenetic strategies synergize with PD-L1/PD‑1 targeted cancer immunotherapies to enhance antitumor responses. Acta Pharm Sin B 10(5):723–733PubMedCrossRef
54.
Zurück zum Zitat Zhou L et al (2020) Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD‑1 Resistance in Head and Neck Cancer. Clin Cancer Res 26(1):290–300PubMedCrossRef Zhou L et al (2020) Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD‑1 Resistance in Head and Neck Cancer. Clin Cancer Res 26(1):290–300PubMedCrossRef
55.
Zurück zum Zitat Goswami S et al (2018) Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest 128(9):3813–3818PubMedPubMedCentralCrossRef Goswami S et al (2018) Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest 128(9):3813–3818PubMedPubMedCentralCrossRef
56.
57.
Zurück zum Zitat Belmontes B et al (2024) AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers. Cancer Discov Belmontes B et al (2024) AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers. Cancer Discov
58.
Zurück zum Zitat Engstrom LD et al (2023) MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer. Cancer Discov 13(11):2412–2431PubMedPubMedCentralCrossRef Engstrom LD et al (2023) MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer. Cancer Discov 13(11):2412–2431PubMedPubMedCentralCrossRef
59.
Zurück zum Zitat Baretti M et al (2024) Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial. Nat Commun 15(1):9801PubMedPubMedCentralCrossRef Baretti M et al (2024) Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial. Nat Commun 15(1):9801PubMedPubMedCentralCrossRef
Metadaten
Titel
Epigenetische Therapien in der Krebsbehandlung: Chancen und Herausforderungen
verfasst von
Prof. Dr. med. Elisabeth Hessmann
Prof. Dr. med. Günter Schneider
Publikationsdatum
06.01.2025
Verlag
Springer Medizin
Schlagwörter
Epigenetik
Onkologie
Erschienen in
Forum
Print ISSN: 0947-0255
Elektronische ISSN: 2190-9784
DOI
https://doi.org/10.1007/s12312-024-01411-z

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