EZH2 wild-type

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.

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.

Herein, a series of quinolinone derivatives were designed and synthesized based on the structure of Tazemetostat as the lead compound. Compound 9 l (EZH2WT IC50 = 0.94 nM) showed stronger antiproliferative activity in HeLa cells than the lead compound. Moreover, compound 9e (EZH2WT IC50 = 1.01 nM) significantly inhibited the proliferation and induced apoptosis in A549 cells.

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

P1, N=64, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

The market approval of Tazemetostat (TAZVERIK) for the treatment of follicular lymphoma and epithelioid sarcoma has established "enhancer of zeste homolog 2" (EZH2) as therapeutic target in oncology...These inhibitors interact in a more entropy-driven fashion and show the most persistent effects in cellular washout and antiproliferative efficacy experiments. Our work provides mechanistic insights for the largest cohort of EZH2 inhibitors reported to date, demonstrating that-among several other binding parameters-target residence time is the best predictor of cellular efficacy.

Other epigenetic therapies, such as tazemetostat and belinostat, are approved for use in follicular and T-cell lymphoma, respectively, but have limited single agent activity in DLBCL. In summary, these data propose YF2 combination epigenetic therapy as a means to increase immunogenicity in CBP/p300- and EZH2-mutated DLBCL. While our preliminary mouse experiment provided promising initial results, an expanded study is underway to statistically confirm the exciting trends that we observed.

Methods and Through short-term killing assays, we compared CART19 alone to CART19 combined with the EZH2 inhibitor tazemetostat (taz), and demonstrated that taz enhances CART19 tumor killing of DLBCL cell lines [OCI-Ly18 and Toledo (with wild-type EZH2) and SU-DHL-4 (with mutant EZH2)]...We retrospectively analyzed a cohort of large B-cell lymphoma patients treated with commercial CART19 (tisagenlecleucel and axicabtagene ciloleucel) at the University of Pennsylvania between January 2018 and March 2023 for response (Lugano criteria) according to their EZH2 mutational status... Our data demonstrate that modulation of EZH2 enhances CART19 immunotherapy in preclinical models of lymphoma. EZH2 inhibition rewires lymphoma immunogenicity, making tumor cells more susceptible to CART19 killing and reducing CART19 terminal differentiation. By understanding and modulating the interplay between tumor and CART cells, we can unlock the full potential of CART19 immunotherapy in DLBCL/FL patients, aiming at long-lasting treatment outcomes.

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or with R/R FL who have no satisfactory alternative treatment options. Although the primary endpoint was not met due to missing BM assessments, TAZ + RCHOP combination demonstrated a promising complete metabolic response rate of 79% in this high-risk frontline FL population, with a manageable safety profile, after vincristine dose was reduced.

P2, N=55, Not yet recruiting, Epizyme, Inc.

P1, N=64, Recruiting, National Cancer Institute (NCI) | Initiation date: Dec 2022 --> Mar 2023

Results The combination of lenalidomide and rituximab, also referred to as R2 , represents today a standard treatment option for patients with relapsed FL, based on results of the randomized phase III trial AUGMENT...The safety and efficacy of epcoritamab, a subcutaneous CD3/CD20 bispecific antibody, has been explored in combination with R2 in 66 patients with relapsed and 36 with previously untreated FL (grade 1 to 3A) in a phase I/II trial (Falchi L et al, ASH 2022).1 No synergistic toxicity was observed, while CR rates were 80% or higher, independently from the line of therapy...While no synergistic toxicity was observed, CR rate remained unchanged as compared to historical data with R2 at 30% (Strati P et al, ASH 2022).3 However, when used in the frontline setting and with a pre-dose of single agent acalabrutinib, in a phase II study including 24 patients with FL, a CR rate higher than 90% has been reported (Strati P et al, EHA 2023).4 Of interest, the combination of a more potent BTK inhibitor, zanubrutinib, with obinutuzumab, an anti-CD20 monoclonal antibody able to better mediate antibody-dependent cellular phagocytosis than rituximab, has shown increased CR rate, from 19% to 37%, as compared to single agent obinutuzumab in the phase II study ROSEWOOD, including 217 patients with relapsed FL (Zinzani PL et al, ASCO 2022).5 This has led to an ongoing randomized phase III trial, comparing this combination to R2 in the relapsed setting. Finally, due to the role played by epigenetic changes in the pathophysiology of iNHL, the combination of tazemetostat, an EZH2 inhibitor approved for the treatment of relapsed FL, has also been investigated...Beyond the novel combinations outlined in this abstract, multiple trials are currently investigating agents with alternative mechanism of actions, including anti-CD19 monoclonal antibodies, anti-CD79b antibody-drug conjugates and novel immunomodulatory agents S111 and allogeneic cellular therapies. The therapeutic landscape of iNHL is soon to significantly change.

The in-depth spatio-temporal analysis identified EZH2 mutations in a considerably higher proportion of patients than previously reported. This expands the subset of FL patients who most likely would benefit from EZH2 inhibitor therapy.

We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.

P1, N=64, Recruiting, National Cancer Institute (NCI) | N=48 --> 64

P1, N=48, Recruiting, National Cancer Institute (NCI) | N=36 --> 48

P1, N=36, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Concurrent chromosome 7 abnormalities (12%) were also associated with significantly worse OS (median OS- 20.8 vs. 35.5 months, p = 0.002) in EZH2mut MDS. Future clinical trials should explore the potential role of novel targeted therapies in improving outcomes in patients with EZH2mut MDS.

P1, N=36, Not yet recruiting, National Cancer Institute (NCI)

XNW5004 was safety, well tolerated, and efficacy in pts with different types of lymphomas despite high disease burden, with encouraging preliminary anti-lymphoma activity observed. These data support ongoing dose-escalated phase , with multiple cohort expansions at multiple doses. Internal Study identifier: XNW5004-I/II-01.

Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.

P1/2, N=420, Completed, Epizyme, Inc. | Active, not recruiting --> Completed