Drug screening identified therapeutic candidates, including Tazemetostat for EZH2 and lithium compounds for GSK3β, underscoring their potential for targeted treatment. These findings provide novel insights into the complexity of HCC pathogenesis, suggesting that the identified hub genes could serve as diagnostic or prognostic biomarkers and therapeutic targets. While bioinformatics-driven, this study offers a strong basis for future clinical validation to advance precision medicine in HCC.

Furthermore, genetic and epigenetic events influencing response to molecularly targeted therapies, such as mogamulizumab and valemetostat, have also been identified. Collectively, these insights underscore the clinical importance of assessing genetic alterations. This review highlights the latest insights into the genetic landscape of ATLL and their clinical implications, which will facilitate the development of future strategies for targeted and personalized therapy.

P1, N=64, Suspended, National Cancer Institute (NCI) | Trial completion date: Mar 2025 --> Sep 2026 | Trial primary completion date: Mar 2025 --> Sep 2026

P2, N=33, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

P2, N=62, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Feb 2026

Our findings revealed that GSK126 induced apoptosis and autophagy, evidenced by increased markers like cleaved caspase-3 and LC3-II, and decreased cellular migration, through downregulation of the Fuse Binding Protein 1 (FBP1)/C-Myc axis. These findings suggest GSK126 as a promising therapeutic against osteosarcoma, offering a dual action of promoting cell death and hindering migration.

Notably, the EZH2 inhibitor Tazemetostat (EPZ-6438) exhibits greater sensitivity in cells with higher ZCCHC8 expression. Altogether, our findings demonstrate a novel mechanism that the NEXT complex regulates H3K27me3 levels by degrading nascent G4/U-Rich lncRNAs in cancer cells.

EZH2-targeted therapies have been successfully used to treat patients with follicular lymphoma and epithelioid sarcoma, but their clinical use in melanoma has not been described. Here, we describe a pediatric patient with multiply relapsed melanoma harboring an EZH2 A692V missense mutation, treated adjuvantly with the EZH2 inhibitor tazemetostat, who experienced a prolonged relapse-free survival.

In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers.

Experimental validation further indicated that the combination of BRD4 inhibitor ZBC260 and EZH2 inhibitor CPI-169 synergistically enhanced apoptosis in HCC. Collectively, this study provides a scientific rationale for early HCC diagnosis and personalized therapy, offering new insights into drug resistance in treatment.

P1, N=24, Not yet recruiting, University of Utah

P1, N=30, Recruiting, Lan Coffman | Trial completion date: Aug 2029 --> Aug 2028 | Trial primary completion date: Jan 2027 --> May 2025

P2, N=25, Completed, Daiichi Sankyo Co., Ltd. | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Oct 2024

P1, N=100, Active, not recruiting, Daiichi Sankyo Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2026

Here we undertook the simultaneous evaluation of two epigenetic drugs targeting EZH2 methyltransferase activity and BRD4-mediated control of MYC transcription, CPI169 and CPI203, using preclinical models of DLBCL and FL with distinct EZH2 mutational status. Gene expression profile, exploratory data analysis, and siRNA screening identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2, as a crucial factor involved in the efficacy of MYC/EZH2 dual targeting both in vitro and in vivo. Altogether, our results provide first pre-clinical evidence that simultaneous targeting of MYC and EZH2 is a safe and efficient approach that can be monitored by specific biomarkers, in aggressive lymphoid tumors of germinal center origin.

P1, N=24, Recruiting, Memorial Sloan Kettering Cancer Center

P1/2, N=58, Active, not recruiting, Epizyme, Inc. | Enrolling by invitation --> Active, not recruiting | N=100 --> 58

EZH2i reduced the expression of DNA repair genes and increased the expression of p53-dependent pro-apoptotic factors. EZH2i plus Carboplatin is a promising combination treatment for AVPC.

P2, N=141, Active, not recruiting, The Lymphoma Academic Research Organisation | Trial completion date: Oct 2024 --> Oct 2026

P2, N=42, Completed, Hutchmed | Active, not recruiting --> Completed | Trial completion date: Jun 2025 --> Nov 2024

P2, N=61, Completed, Hutchmed | Recruiting --> Completed | N=140 --> 61 | Trial completion date: Dec 2026 --> Dec 2024 | Trial primary completion date: May 2026 --> Dec 2024

Furthermore, KDM2B knockdown increased the level of the transcriptionally repressive histone mark H3K27me3 on the key lytic gene pp38 promoter, accompanied by suppression of pp38 expression and reduced latent-to-lytic switch in MDV-latently infected cells, while treatment of cells with H3K27me3 inhibitors (GSK126 and Tazemetostat) markedly promoted the expression of pp38 and MDV reactivation from latency. Mechanistically, miR-M6-5p epigenetically suppressed the expression of the viral lytic gene pp38 by directly targeting the histone demethylase KDM2B. These findings will advance our understanding of the role of virus-encoded miRNA in the regulation of viral latency and will help guide the development of novel strategies for the effective control of MDV.

P1, N=16, Not yet recruiting, Pfizer | Trial completion date: Apr 2025 --> Sep 2025 | Initiation date: Dec 2024 --> Apr 2025 | Trial primary completion date: Apr 2025 --> Sep 2025

Here we present an unusual case of a patient with renal medullary carcinoma with metastasis to the brain following treatment which included tazemetostat, an EZH2 inhibitor...As renal medullary carcinoma has been known to cleverly utilize adaptive mechanisms for survival, we propose that such cell plasticity seen in this case may have been provoked by the use of a drug that alters the epigenetic signature of the tumor cells. Thus, careful assessment of tumor biology following novel therapeutic treatment options must be performed in order to note such unexpected consequences of treatment.

P3, N=900, West China Hospital of Sichuan University; West China Hospital of Sichuan University

P3, N=120, Not yet recruiting, Evopoint Biosciences Inc.

P2, N=32, Active, not recruiting, Northwestern University | Recruiting --> Active, not recruiting

Notably, EZH2 inhibitors have shown great efficacy in antitumor therapy and have also demonstrated promising results in antiviral, anti-inflammatory, antisclerotic, bone protection, and nerve injury pain applications. The insights gained from this analysis could provide valuable guidance for future drug design and optimization of EZH2 inhibitors, potentially expediting the discovery of new inhibitors or degraders targeting EZH2.

GD2 expression in sarcoma cells was also evaluated in response to an enhancer of zeste homolog 2 (EZH2) inhibitor (Tazemetostat)...Our preclinical data strongly suggest that CAR.GD2 T-cells hold promise as a potential therapeutic option for the treatment of patients with GD2-positive sarcomas. Strategies to tackle hostile immunosuppressive MDSC are desirable to optimize CAR.GD2 T-cell activity.

P1, N=6, Completed, Pfizer | Active, not recruiting --> Completed

P1/2, N=58, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Nov 2025

P1/2, N=102, Terminated, Epizyme, Inc. | Active, not recruiting --> Terminated; Sponsor decision, no safety concern

Molecular docking analyses predicted most probable inhibitors of EZH2. We employed several predictive analysis tools and identified GSK343, as a promising inhibitor of EZH2.

Therefore, EZH2 inhibition enhances CAR-T cell efficacy through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This approach is currently being evaluated in two clinical trials, NCT05934838 and NCT05994235, to improve immunotherapy outcomes in B cell lymphoma patients.

EZH2-mediated H3K27 trimethylation silences miR-137 in CRC cells by increasing chromatin compaction, reversible by EZH2 siRNA or inhibitor GSK343...It regulates the Wnt signaling pathway by targeting RNF4, leading to c-Myc and β-catenin destabilization. Restoring miR-137 or inhibiting RNF4 suppresses CRC cell proliferation, migration, invasion, and tumor growth, highlighting its therapeutic potential in CRC.

P1, N=33, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

Our further experiments evidences indicated that ETV5 facilitated cell proliferation and reduced sensitivity to GSK126 via regulating EZH2. Collectively, this study comprehensively elucidates the carcinogenic effects and molecular mechanisms of ETV5 in tumorigenesis and development, and provides theoretical basis and guidance for tumor diagnosis, targeted therapy for ETV5 and clinical epigenetic drug research.

P2, N=50, Not yet recruiting, Evopoint Biosciences Inc.

P1/2, N=307, Enrolling by invitation, Evopoint Biosciences Inc.

P2, N=42, Active, not recruiting, Hutchmed | Recruiting --> Active, not recruiting | Trial completion date: Feb 2024 --> Jun 2025 | Trial primary completion date: Jun 2023 --> Nov 2024

Exposure to GSK343 or ATRA results in inhibition of cell proliferation and induction of cellular senescence, where GSK343 shows a dominant effect. The Figure was created with Biorender.com.

Treatment with the EZH2 inhibitor tazemetostat restored expression of genes involved in cysteine-methionine metabolism and lipid homeostasis, while suppressing angiogenesis and oxidative stress-related genes...Functionally, EZH2 inhibition dose-dependently reduced cell viability and increased lipid peroxidation in HCC cells. Our findings reveal a novel epigenetic mechanism controlling lipid peroxidation and ferroptosis susceptibility in HCC, providing a rationale for exploring EZH2-targeted therapies in this malignancy.