belinostat + tazemetostat

**Belinostat + tazemetostat** is an investigational combination therapy of two epigenetic modulators for relapsed/refractory non-Hodgkin lymphoma (NHL), particularly germinal center B-cell lymphomas (GCB-DLBCL, follicular lymphoma, transformed disease) and T-cell lymphomas with mutations in EZH2, CREBBP, or EP300. **Belinostat**, a **small molecule histone deacetylase inhibitor (HDACi)**, blocks histone deacetylases to increase histone acetylation, promoting cancer cell death, inhibiting angiogenesis, and enhancing sensitivity to other therapies. **Tazemetostat**, a **small molecule EZH2 inhibitor**, targets the histone methyltransferase EZH2 to reduce H3K27 trimethylation, disrupting gene expression and cell proliferation in EZH2-mutated cancers. Preclinical synergy shows dual modulation of histone acetylation and methylation induces profound epigenetic changes, T-cell activation, and tumor regression in DLBCL and T-cell lymphoma models, supporting the ongoing NCI/CTEP ETCTN P10500 phase 1 trial (NCT05627245).[1][2]