P1/2, N=203, Not yet recruiting, Dizal Pharmaceuticals

P2, N=900, Not yet recruiting, Gustave Roussy, Cancer Campus, Grand Paris

Therapeutic targeting of H3K27me3 with EZH2-selective inhibitors such as tazemetostat has shown clinical benefit in lymphoma; however, their efficacy is limited by functional redundancy with EZH1. The dual EZH1/2 inhibitor valemetostat overcomes this limitation by reactivating tumor suppressor genes, achieving durable responses in ATL and peripheral T-cell lymphoma (PTCL). Nonetheless, therapeutic resistance can emerge through PRC2 gatekeeper mutations and compensatory DNA methylation. These findings underscore the value of targeting the dysregulated epigenome and support the continued clinical development of dual EZH1/2 inhibitors.

Treatment with the dual EZH1/2 inhibitor UNC1999 and 5-azacytidine reactivated these PRC2 target genes, specifically in AML-HSPCs, toward normal gene expression patterns. These findings suggest that targeting Polycomb repression offers a promising epigenetic strategy for improving outcomes in KMT2A-rearranged AML.

P1, N=60, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

P2, N=155, Active, not recruiting, Daiichi Sankyo | Trial completion date: Sep 2025 --> Feb 2027

P1/2, N=203, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P1, N=60, Not yet recruiting, Daiichi Sankyo

P1/2, N=188, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P1/2, N=188, Not yet recruiting, Novartis Pharmaceuticals

Moreover, mutp53 was downregulated, p21 was upregulated, and CHK1 was reduced, increasing DNA damage and leading to a stronger impairment of pancreatic cancer cell survival compared with single-agent treatments. Our results reveal that combining epigenetic drugs such as Valemetostat and SAHA could be exploited to target mutp53 and improve the outcome of treatments for aggressive tumors harboring it, such as in pancreatic cancer.

Collectively, these findings reveal a coordinated role for EZH1-dependent H3K27me1 and DNA methylation in sustaining oncogenic transcriptional programs and provide strong rationale for advancing dual EZH1/2 inhibitors for combination epigenetic cancer therapy. Dual EZH1/2 inhibitors reduce all three H3K27 methylation states and robustly synergize with DNMT inhibitors.EZH1 mediates H3K27me1 deposition at deeply Polycomb-marked regions in the absence of EZH2.EZH inhibitors induce a bivalent repressive state marked by DNA methylation and H3K27ac that limits p300/CBP-dependent transcription.DNMT inhibitor-induced "epigenetic switching" is more vulnerable to dual EZH1/2 blockade than selective EZH2 inhibition.Combined EZH1/2 and DNMT inhibition redistributes H3K27ac away from pro-growth oncogenic signaling genes and towards bivalent genes.Suppression of oncogenic signaling by dual DNMTi and EZH1/2 inhibition is a key efficacy signature of this drug combination.