EZH2 mutation

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

Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components...Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their use in combination with standard chemotherapy or immunotherapy has great potential for improving patient outcomes in cancers driven by PRC2 dysregulation.

Notably, we identify a therapeutic vulnerability in TNBC cells whereby combination treatment with ABL allosteric inhibitors and EZH2 inhibitors elicits a synergistic decrease in TNBC cell survival in vitro, and impairs TNBC metastasis, prolonging survival of tumor-bearing mice treated with the combination therapy. ABL Kinases indirectly impact EZH2 catalytic activity by blocking a signaling cascade that leads to changes in the phosphorylation, protein interactions, and function of the PRC2 catalytic component EZH2 in TNBC.

Furthermore, we demonstrated the effectiveness of this epigenetic combination strategy in a xenograft model, which resulted in significant abrogation of tumor growth. Together, our studies provide pre-clinical proof-of-concept for an epigenetic combination therapy to overcome resistance and improve durability of response for the treatment of B-cell lymphoma, warranting clinical investigation and illustrating an important convergent role of EZH2 and DOT1L in B cell lymphomagenesis.

PTEN presence, BCL2 mutations, and low or undetectable baseline IL-2 levels were associated with improved patient survival following treatment with C + R, supporting a potential role for these biomarkers in guiding treatment selection for patients with indolent non-Hodgkin lymphoma.

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.

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.

P2, N=63, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Feb 2025 --> Feb 2027 | Trial primary completion date: Feb 2025 --> Feb 2027

Donor cell-derived hematologic neoplasms are rare but significant complications after HSCT. Early diagnosis and intervention are crucial to improving patient prognosis. Further studies are needed to better understand the pathogenesis of this condition and develop more effective therapeutic strategies.

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

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

EZH2 expression can affect the prognosis of patients with liver cancer. Our pathological model could predict EZH2 expression and prognosis of patients with HCC with high accuracy and robustness, making it a new and potentially valuable tool.

Positivity for H3K27me3, especially double positivity for H3K27me3 and EZH2, could be a poor prognostic factor for astrocytoma, IDH-mutant. These results suggest the utility of H3K27me3 and EZH2 as candidate markers for estimating the malignancy of astrocytoma, IDH-mutant.

These findings suggest that the Ezh2Y641F mutation may alter immune regulatory pathways, cell differentiation and apoptosis, with potential implications for disease progression. Our results highlight the critical role of mutation timing and cellular context in EZH2-driven hematopoietic disease, resulting in distinct downstream changes that shape the oncogenic impact of EZH2.

Her favorable response to conventional therapy underscores the importance of molecular phenotyping in the treatment of this disease. The continued use of NGS to gather relevant molecular data is crucial for further understanding the molecular phenotype and prognosis of such atypical ALL cases.

We aimed to validate the prognostic value of the 2022 ELN classification (ELN22) evaluating 1,570 newly diagnosed AML patients (median age, 56 years) treated with cytarabine-based intensive chemotherapy regimens...In conclusion, the ELN22 risk stratification improves prognostic discrimination in a large cohort of intensively treated AML patients. Given the heterogeneous outcome in patients with MR gene alterations, ranging between those of intermediate and adverse risk patients, we suggest reevaluation of risk allocation in these patients.

P2, N=55, Not yet recruiting, Epizyme, Inc. | Trial completion date: Sep 2027 --> Apr 2029 | Trial primary completion date: Sep 2027 --> Apr 2029

According to early findings, NGS panels are extremely effective instruments that provide an entirely new viewpoint on the disease for particular individuals. Future prognostications will depend more on NGS because those who exhibit normal cytogenetics may additionally have gene mutations.

P1, N=64, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

Extended-interval dosing of tazemetostat transformed a partial response into a complete response. Thus, tazemetostat is effective for the treatment of multiple relapsed FL in the leukemic phase.

Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics.

We present a case of a man in his late 50s with RDD who experienced worsening cytopenias, including severe neutropenia and respiratory distress, despite an initial positive response to steroids, rituximab and lenalidomide. Sirolimus was initiated and led to complete radiological remission of the disease. This case adds strength to the growing evidence supporting the efficacy of sirolimus in refractory RDD cases.

P1, N=272, Active, not recruiting, Jiangsu HengRui Medicine Co., Ltd. | Recruiting --> Active, not recruiting | Trial completion date: Aug 2023 --> Aug 2026 | Trial primary completion date: Feb 2023 --> Feb 2026

EZH2 mutation is associated with VM development in breast cancer patients. The EZH2K515R mutation leads to VM and a poor prognosis by enhancing proliferation and invasion and inhibiting apoptosis in breast cancer cells.

P1, N=64, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

In conclusion, using a customized panel, we characterized the mutational landscape of a large cohort of Mexican DLBCL patients. These results need to be confirmed in further studies.

High expression of BMI1 and of USP22 might be a poor prognostic factor in DLBCL, and might represent the target for novel inhibitors.

EZH2 G553C polymorphism contributes to the prediction of brain metastasis of lung cancer, in which G allele carriers are more prone to brain metastasis.

P1/2, N=254, Recruiting, Haihe Biopharma Co., Ltd. | N=168 --> 254

Moreover, we observed a tendency of CHIP-positive patients to achieve a suboptimal response to therapy compared to those without. A sub-clone dynamic of high-fitness mutations over time was confirmed.

We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

Whole transcriptome analysis showed that overexpression of HOXA9 differentiated t(X;21) from both controls and t(8;21)-positive AML. In conclusion, we characterized a new recurrent reciprocal t(X;21)(p11.4;q22.12) chromosome translocation in MDS and AML, generating simultaneous BCOR and RUNX1 deletions rather than a fusion gene at the genomic level.

Most commonly used agents include hydroxyurea, interferon, Janus kinase inhibitors, and hypomethylating agents, though none are disease-modifying. Actionable mutations (NRAS/KRAS, ETNK1) have also been identified, supporting novel agents targeting involved pathways. Preclinical and clinical studies evaluating new drugs (e.g., fedratinib, phase 2) and combinations are detailed.

In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability...Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.

P3, N=612, Recruiting, Epizyme, Inc. | Trial completion date: Mar 2029 --> Apr 2032 | Trial primary completion date: Mar 2026 --> Sep 2029

P1, N=32, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Aug 2024 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Aug 2025

P2, N=80, Recruiting, Mayo Clinic | N=55 --> 80

P2, N=55, Recruiting, Mayo Clinic | Trial completion date: Mar 2024 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Dec 2025

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

P1/2, N=168, Recruiting, Haihe Biopharma Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

p53 mutant pattern is due to TP53 mutation. MCL patients with EZH2 expression or TP53 mutation show inferior outcome and when both are present, patients have dismal outcome.

P2, N=55, Not yet recruiting, Epizyme, Inc. | Initiation date: Dec 2023 --> Sep 2024