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Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
Targeted small molecule inhibitors—multiple intracellular signaling pathways are therapeutically targetable in FL. Abnormal signaling in FL through the PI3K/AKT/mTOR pathway can be targeted using the PI3K class of small molecular inhibitors (including idelalisib [PI3Kδ], copanlisib [PI3Kα/δ], and duvelisib [PI3Kδ/γ]). These agents have reasonable response rates (approximately 30%–50%); however toxicity (particularly gastrointestinal and pulmonary) can be an issue. Approximately 30% of patients with relapsed/refractory FL harbor activating mutations in EZH2 which results in a “locking in” of the malignant cell into the germinal center transcriptional program. Tazemetostat is an oral inhibitor of EZH2 and shows relatively high response rates in EZH2-mutated FL (approximately 70%) and is generally well-tolerated. Other targeted therapies include BTK inhibitors (e.g., ibrutinib) and BCL2 inhibitors (e.g., venetoclax).
Atypical Teratoid / Rhabdoid Tumors – AT/RT
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Michael C. Frühwald, Jaclyn A. Biegel, Susan N. Chi
Epigenetic targeting is currently one of the most active areas of research in drug development. The inhibition of enzymatic activities involved in epigenetic silencing by histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and enhancer of zeste homolog 2 (EZH2) is being tested in multiple active clinical trials. The antagonistic relationship between SWI/SNF and the polycomb repressive complex 2 (PRC2) plays a critical role in gene transcription and makes it an attractive target for therapy in AT/RT.114 EZH2 is critical for normal development and lineage-specific differentiation. Overexpression of EZH2 leads to the maintenance of a pluripotent state.115 Preclinical studies reported elevated expression of EZH2 in SMARCB1-deficient cells and demonstrated apoptosis in EZH2-depleted rhabdoid tumor cell lines.116 Further experimentation demonstrated upregulation of EZH2 following SMARCB1 loss. This was accompanied by widespread trimethylation of histone H3K27 and repression of p16INK4.117 Potent, selective EZH2 inhibitors have been developed. One of these, tazemetostat (EPZ-6438), is a selective orally bioavailable inhibitor of EZH2’s enzymatic activity.
Weaver Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Located on chromosome 7q36.1, the enhancer of zeste, drosophila, homolog 2 gene (EZH2) comprises multiple alternative transcripts, the longest of which has 20 exons and encodes a 751-amino-acid histone methyltransferase (EZH2) with a critical SET [su(var)3–9, enhancer of zeste, trithorax] domain, a pre-SET CXC domain, and two additional SANT (Sw13, Ada2, N-cor TFIIIB) domains. EZH2 constitutes the catalytic subunit of the polycomb-repressive complex 2 (PRC2), which also includes additional core components SUZ12 (suppressor of zeste 12) and EED (embryonic ectoderm development). As a highly conserved epigenetic modifying complex, PRC2 induces trimethylation of histone H3 at lysine 27 (resulting in H3K27me3), which serves as an epigenetic signal for chromatin condensation and transcriptional repression and contributes to the regulation of chondrocyte proliferation and hypertrophy in the growth plate [9]. Functional loss of any of the components (i.e., EZH2, SUZ12, and EED) compromises the enzymatic activity of PRC2 and subsequent reduction of H3K27me3, leading to transcriptional activation of loci to which H3K27me3 is bound [10–12].
Inhibition of EZH2 mitigates peritoneal fibrosis and lipid precipitation in peritoneal mesothelial cells mediated by klotho
Published in Renal Failure, 2023
Qinglian Wang, Jingshu Sun, Rong Wang, Jing Sun
Enhancer of zeste homolog 2 (EZH2) is a histone lysine methyltransferase that catalyzes the methylation of histones. Histone modification leads to altered chromatin structure and affects the accessibility of transcription factor DNA promoters. Currently, research on EZH2 is mainly focused on its role in tumorigenesis, and inhibition of EZH2 activity has become a new strategy for antitumor therapy. In addition, studies also revealed that EZH2 had a close relationship with hepatic fibrosis, kidney fibrosis and bone marrow fibrosis. In our previous research, we found that GSK343 (an inhibitor of EZH2) exhibited protective effects in high glucose-treated human peritoneal mesothelial cells (HPMCs) [7]. However, whether it plays a role by reducing lipid deposition is still unclear. In the present study, we further explored the related mechanism in peritoneal fibrosis.
Identifying prognostic gene panels in acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Joaquin Sanchez-Garcia, Josefina Serrano, Esther Prados de La Torre, Juana Serrano-López, Clara Aparicio-Perez, E Barragán, Pau Montesinos
Additional sex combs-like 1 (ASXL1) gene is located at 20q11 encoding a chromatin-regulator, which is mutated in clonal hematopoiesis of indeterminate potential (CHIP) as well as in all myeloid malignancies including AML (in approximately 20% of cases) conferring adverse prognosis [101]. EZH2 is gene located at 7q36 encoding a histone methyltransferase component of the Polycomb group (PcG) of proteins acting as a transcriptional repressor [102]. BCOR gene located at Xp14 codes a protein interacting corepressor of BL6 and it has been reported to be rare but recurrently mutated in AML found in up to 15% of AML with normal karyotype conferring adverse prognosis [103]. STAG2 gene located at Xq25 encodes a subunit of the cohesion complex responsible for the separation of chromatids during mitoses. Mutations leading to loss of function are detected in AML (~5%) and MDS (~20%) [104] without clear impact on outcomes.
Preclinical pharmacokinetics and metabolism of MAK683, a clinical stage selective oral embryonic ectoderm development (EED) inhibitor for cancer treatment
Published in Xenobiotica, 2022
Ji Yue (Jeff) Zhang, Jiangwei Zhang, Michael Kiffe, Markus Walles, Yi Jin, Joachim Blanz, Jerôme Dayer, Arevalo Sanchez, Chunye Zhang, Lijun Zhang, Ying Huang, Counde Oyang
Histone modification is one of the key epigenetic mechanisms in regulating many fundamental cellular processes. Polycomb Repressive Complex 2 (PRC2) is a key transcriptional repressor that plays an essential role in regulating gene expression through its lysine methyltransferase activity on histone H3 lysine 27 (H3K27) (Xu et al. 2010; Margueron and Reinberg 2011). The functional core of PRC2 that essential to catalyse the methylation of H3K27 consists of one of the SET-domain-containing histone methyltransferases enhancer of zeste (EZH2 or EZH1), embryonic ectoderm development (EED), suppressor of zeste (SUZ12), and the CAF1 histone-binding proteins RBBP4 and RBBP7. Dysregulation of PRC2 is observed in multiple human cancers. The catalytic subunit EZH2 is overexpressed in a wide range of human cancers and is associated with cell proliferation and poor prognosis in patients (Varambally et al. 2002; McCabe and Creasy 2014; Kim and Roberts 2016). Moreover, gain-of-function mutations in EZH2 have been implicated in follicular lymphoma, diffuse large B cell lymphoma, parathyroid carcinoma, and melanoma, while functionally similar mutations in EZH1 have been reported in autonomous thyroid adenomas. These mutations increase the methyltransferase activity of PRC2 thereby increasing the level of H3K27me3 in cells and aberrantly repressing gene expression (Audia and Campbell 2016).