EPZ011989 / Eisai, Ipsen - LARVOL DELTA

Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia. (PubMed, Cancers (Basel)) - "Despite evidence that EZH2 silencing in MDS/MPN can promote AML pathogenesis, our data demonstrate that the therapeutic inhibition of EZH2 in established AML has the potential to improve survival."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34

ASXL1 Truncating Mutations Drive Leukemic Resistance to T Cell Attack (ASH 2023) - "Treatment with IFNɣ or EPZ011989, an inhibitor of enhancer of zeste-homolog 2 (EZH2), resulted in greater HLA-I in K562 ASXL1c (85.0% vs 50.2% and 89.5% vs 39.3%, respectively, q<0.001) suggesting that ASXL1c acts orthogonally to IFNɣ or EZH2...Specifically, we link DLIr to ASXL1m that suppresses transcription of HLA-I and antigen presentation machinery in myeloid diseases; moreover, its correction restores anti-leukemic CD8+ T-cell cytotoxicity. Ongoing studies will examine additional clinical contexts and the epigenetic mechanisms by which ASXL1m regulates HLA-I expression."

IO biomarker • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • ABL1 • ASXL1 • BCR • CD8 • HLA-B • IKZF1 • RUNX1

EZH2 inhibition induces blast differentiation in acute myeloid leukemia (AACR 2022) - "However, we hypothesized that in AML patients without EZH2 mutations, loss of EZH2 function may produce a phenotype that would allow for therapeutic targeting without influencing normal hematopoiesis.We used EPZ011989 (EPZ), an EZH2 inhibitor tool compound, to inhibit H3K27me3 in our studies...Furthermore, our preliminary data suggests that daily treatment with 150 mg/kg of EPZ results in a survival advantage and reduced disease burden in the MOLM-13-luciferase murine xenograft model.Despite loss of function EZH2 mutations portending poor outcomes in myeloid malignancies, we demonstrate that pharmacologic EZH2 inhibition reduces AML blast stemness and promotes differentiation into mature myeloid cells. In contrast, no change in normal CD34+ stem cells occurs with EZH2 inhibition, offering the opportunity to selectively target myeloid leukemia."

Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD34 • ITGAM

Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR. (PubMed, Mol Cancer Ther) - "Treatment with EPZ011989, an EZH2 inhibitor, derepressed SLFN11 expression in 361-PBDr and other SLFN11-deficient tumor cells, and increased sensitivity to PBD and PBD-conjugated ADCs, indicating that the suppression of SLFN11 expression is associated with histone methylation as reported. Moreover, we demonstrated that combining an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, AZD6738, with SG3199 or PBD-based ADCs led to synergistic cytotoxicity in either resistant 361-PBDr cells or cells that SLFN11 was knocked down via siRNA. Collectively, these data provide insights into potential development of resistance to PBDs and PBD-conjugated ADCs, and more importantly, inform strategy development to overcome such resistance."

Journal • Ataxia • Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • SLFN • SLFN11

Opportunity for therapeutic expansion in mantle cell lymphoma: Tazemetostat combination synergy status in preclinical MCL models (AACR 2018) - "Robust synergy was observed with glucocorticoid receptor agonists, immunomodulatory drugs, venetoclax and a variety of B-cell receptor pathway modulators in both dosing regimens. In addition, we show that EPZ011989 (an EZH2 tool compound) induces tumor growth inhibition in a MCL xenograft model, and has combination benefit with ibrutinib.Preclinical data suggest that the sensitivity to tazemetostat as a single agent in MCL cell lines can be greatly enhanced in combination with new and emerging therapies. These combination approaches may be worthy of exploration in the clinic for the treatment of MCL."

IO biomarker • Preclinical • Mantle Cell Lymphoma • Mesothelioma

[VIRTUAL] Blocking H3K27me3 methyltransferase or demethylase activity impacts epithelial-mesenchymal plasticity, suppressing tumor growth and metastasis (SABCS 2020) - "We found that the EZH2 inhibitor, EPZ011989, reduced EMP by preventing recovery of epithelial trails in cells exposed to TGFβ, but did not, on its own, induce EMT. However, we found that either inhibition of the H3K27me3-directed demethylases, KDM6A and KDM6B, using GSK-J4 or shRNA knockdown, induced EMT and promoted cellular migration... These results indicate that addition and removal of H3K27me3 is critical for maintenance of cell fate and plasticity. Furthermore, targeting this pathway suppresses breast cancer growth and metastasis in a mouse model of ER-positive breast cancer."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • ER • EZH2 • KDM6A • KDM6B

Epigenetic silencing of chemokine CCL2 represses macrophage infiltration to potentiate tumor development in small cell lung cancer. (PubMed, Cancer Lett) - "Furthermore, in an ectopic engraft model of SCLC, disruption of EZH2/DNMT1 function using the combination treatment of EPZ011989 and Decitabine potently abrogated the inhibition of macrophage infiltration and thus suppressed tumor growth, the effect of which was impaired by CCL2 neutralization or macrophage depletion. Overall, this work provides new insights into the role of macrophages in SCLC and establishes a rationale for constructing novel therapeutic avenues for SCLC patients."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CCL2 • DNMT1 • EZH2

In vivo evaluation of the EZH2 inhibitor (EPZ011989) alone or in combination with standard of care cytotoxic agents against pediatric malignant rhabdoid tumor preclinical models-A report from the Pediatric Preclinical Testing Consortium. (PubMed, Pediatr Blood Cancer) - "Here, we determined whether an inhibitor of EZH2 enhanced the effect of standard of care chemotherapeutic agents: irinotecan, vincristine, and cyclophosphamide. The Pediatric Preclinical Testing Program (PPTP) previously reported the activity of the EZH2 inhibitor tazemetostat (EPZ6438) against xenograft models of rhabdoid tumors. EPZ011989 significantly prolonged time to event in all the six rhabdoid models studied but did not induce tumor regression. The addition of EPZ011989 to standard of care agents significantly improved time to event in at least one model for each of the agents studied, although this effect was observed in only a minority of the combination testing experiments."

Combination therapy • Journal • Oncology • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Solid Tumor • EZH2

[VIRTUAL] MECHANISTIC AND THERAPEUTIC INSIGHTS INTO PRC2 REPROGRAMMING IN BLAST PHASE CML (EHA 2020) - "Dysregulated PRC2 components were targeted in vitro using lentiviral-mediated knockdowns in two myeloid BP-CML cell lines and, in parallel, the efficacy of an EZH2i (EPZ011989) alone and in combination with nilotinib (NIL) in BP-CML CD34+ cells was assessed in vitro and in vivo using murine models. The molecular responses for this drug combination in CP and BP CD34+ cells is currently being examined using RNA-seq. Conclusion Overall, this study provides compelling evidence that PRC2 is a tractable target in both CP- and BP-CML and a rationale for evaluating these in ongoing and future CML clinical trials."

Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ABL1 • CD34 • EZH2 • RBBP4

THE ONCOHISTONE H3.3K27M DRIVES DIFFUSE INTRINSIC PONTINE GLIOMA INDEPENDENT OF FUNCTIONAL EZH2 (SNO 2018) - "Ezh2 deletion in NTv-a; Ezh2f/fmice exacerbated DIPG pathogenesis, indicated by a 2.5-fold higher Ki-67 immunostaining (pEzh2deletion in neurospheres from Ntv-a; Ezh2f/fneonates enhanced cell proliferation as did the addition of EPZ011989. Superimposition of the H3.3K27M mutant histone in this BACKGROUND:, significantly shortened tumor latency, with a median survival of 54 days compared to 70 days in H3.3 wild type histone control group (p<0.05) and 50% incidence of Grade IV tumors. These results suggest that H3K27M may be oncogenic even in the absence of EZH2."

Brain Cancer • Oncology • Sarcoma • Solid Tumor

Nanoformulation of EPZ011989 Attenuates EZH2-c-Myb Epigenetic Interaction by Proteasomal Degradation in Acute Myeloid Leukemia. (PubMed, Mol Pharm) - "The findings provide valuable experimental evidence for the targeted epigenetic therapy of AML. The present results demonstrate an epigenetic regulation-based superior antileukemic therapy."

Journal • BMI1 • EZH2 • ITGAM • PCR

Comparative Assessment of Antitumor Effects and Autophagy Induction as a Resistance Mechanism by Cytotoxics and EZH2 Inhibition in INI1-Negative Epithelioid Sarcoma Patient-Derived Xenograft. (PubMed, Cancers (Basel)) - "The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin-ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition."

Clinical • Journal