Epigenetic Therapies in Cancer

Epigenetic dysregulation contributes to cancer through DNA hypermethylation that silences tumor suppressor genes, histone modification imbalance that alters chromatin accessibility, and mutations in epigenetic regulators including DNMT3A, TET2, IDH1, IDH2, EZH2, and ASXL1. Therapy targets these mechanisms to restore normal gene expression and trigger differentiation or apoptosis.

DNA methyltransferase inhibitors azacitidine and decitabine are standards in higher risk myelodysplastic syndrome and used in elderly acute myeloid leukemia often combined with venetoclax. Histone deacetylase inhibitors vorinostat, romidepsin, and belinostat are approved for cutaneous and peripheral T cell lymphomas. Tazemetostat targets EZH2 in epithelioid sarcoma and follicular lymphoma with EZH2 mutation.

Mutant IDH1 inhibitor ivosidenib and mutant IDH2 inhibitor enasidenib are oral targeted agents that reverse oncometabolite production and induce differentiation in IDH mutant acute myeloid leukemia and IDH1 mutant cholangiocarcinoma. Adverse effects include differentiation syndrome with respiratory and hemodynamic instability, cytopenias, and QT prolongation requiring close monitoring during the first weeks of therapy.