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.

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

P1/2, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2025 --> Sep 2027 | Trial primary completion date: Sep 2025 --> Sep 2027

P1/2, N=100, Recruiting, Haihe Biopharma Co., Ltd. | Trial primary completion date: Apr 2025 --> Oct 2025

No significant adverse effects of valemetostat were observed early after transplantation, in contrast to the increased incidence of severe GVHD and non-relapse mortality reported following allo-HCT after mogamulizumab therapy. These findings suggest that valemetostat is a promising option as a bridging therapy to allo-HCT for aggressive ATL.

The EZH2 histone methyltransferase inhibitors tazemetostat and valemetostat have recently received approval for clinical use in follicular lymphoma and adult T-cell leukemia/lymphoma, respectively. Mechanistically, EZH2 inhibition in B cells depletes the repressive histone modification H3K27me3 while concurrently enhancing the active histone modification H3K27ac, thereby selectively increasing transcriptional activity and facilitating chromosomal translocation formation in the presence of high AID activity or Ligase4 deficiency. These findings highlight the impact of drugs that induce epigenetic changes to influence chromosomal translocations and demonstrate the genetic safety of EZH2 inhibitors as monotherapy while highlighting the increased risk of genomic instability when used in cells prone to translocations, such as B cells with high AID levels or DNA-repair deficiency.

HH2853 is a novel dual EZH1/2 inhibitor that exhibits superior antitumour activity compared to tazemetostat across various preclinical models. A phase II trial of HH2853 in patients with ES is underway. The Science, Technology and Economic Commission of Shanghai Pudong New Area Municipality and Shanghai Haihe Biopharma Co., Ltd.