Initial testing (stage 1) of tazemetostat (EPZ‐6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program

Kurmasheva, Raushan T.; Sammons, Melissa; Favours, Edward; Wu, Jianwrong; Kurmashev, Dias; Cosmopoulos, Katherine; Keilhack, Heike; Klaus, Christine; Houghton, Peter J.; Smith, Malcolm A.

doi:10.1002/pbc.26218

Cited by 91 publications

(56 citation statements)

References 41 publications

(95 reference statements)

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“…This speaks for a role of the non‐catalytic subunit of EZH2 in tumourigenesis and indicates that pharmacological decrease of H3K27me3 may not be the only mechanism by which EZH2 exerts pro‐tumourigenic influence. Along a similar line, it has been found previously that the reduction of H3K27me3 does not correlate with the tumour response when treating rhabdoid tumour xenografts with EZH2 inhibitors [12].…”

Section: The Epigenetic Consequences Of Smarcb1 Alterationssupporting

confidence: 57%

Invited Review: Dysregulation of chromatin remodellers in paediatric brain tumours – SMARCB1 and beyond

Johann

2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 57-72 Dysregulation of chromatin remodellers in paediatric brain tumours -SMARCB1 and beyond Mutations in chromatin remodelling genes occur in approximately 25% of all human tumours (Kadoch et al. Nat Genet 45: 592-601, 2013). The spectrum of alterations is broad and comprises single nucleotide variants, insertion/deletions and more complex structural variations. The single most often affected remodelling complex is the SWI/SNF complex (SWItch/sucrose non-fermentable). In the field of paediatric neuro-oncology, the spectrum of affected genes implicated in epigenetic remodelling is narrower with SMARCB1 and SMARCA4 being the most frequent.The low mutation frequencies in many of the SWI/SNF mutant entities underline the fact that perturbed chromatin remodelling is the most salient factor in tumourigenesis and could thus be a potential therapeutic opportunity. Here, I review the genetic basis of aberrant chromatin remodelling in paediatric brain tumours and discuss their impact on the epigenome in the respective entities, mainly medulloblastomas and rhabdoid tumours. Aberrations described in-Rhabdoid tumours eletions/SNVs (95% of all cases) -rare entities: INI1 deficient chordomas (10-20% of all cases), CRINET (all cases) Figure 1. An overview on SWItch/sucrose non-fermentable aberrant paediatric entities. CRINET, cribriform neuroepithelial tumours. Dysregulation of chromatin remodellers in paediatric neurooncology 61 CNS CRINET Point mutations CNS CRINET, cribriform neuroepithelial tumours.

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Section: The Epigenetic Consequences Of Smarcb1 Alterationssupporting

confidence: 57%

Invited Review: Dysregulation of chromatin remodellers in paediatric brain tumours – SMARCB1 and beyond

Johann

2020

Neuropathology Appl Neurobio

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“…For instance, miR‐101a expression decreases and Ezh2 expression increases during progression of prostate cancer (Varambally et al ., ) and bladder cancer (Friedman et al ., ). The Ezh2 inhibitor tazemetostat is currently undergoing clinical trials to test safety and efficacy in treating several different cancers (Kurmasheva et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Amygdalar expression of the microRNA miR‐101a and its target Ezh2 contribute to rodent anxiety‐like behaviour

Cohen

Jackson

Ballestas

et al. 2017

Eur J of Neuroscience

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A greater understanding of neural mechanisms that contribute to anxiety is needed in order to develop better therapeutic interventions. The current study interrogates a novel molecular mechanism that shapes anxiety-like behavior, demonstrating that the microRNA miR-101a-3p and its target, enhancer of zeste homolog 2 (Ezh2) in the amygdala, contribute to rodent anxiety-like behavior. We utilized rats that were selectively-bred for differences in emotionality and stress reactivity, showing that high novelty responding (HR) rats, which display low trait anxiety, have lower miR-101a-3p levels in the amygdala compared to low novelty responding (LR) rats that characteristically display high trait anxiety. To determine if there is a causal relationship between amygdalar miR-101a-3p and anxiety behavior, we used a viral approach to over-express miR-101a-3p in the amygdala of HR rats and test whether it would increase their typically low levels of anxiety-like behavior. We found that increasing miR-101a-3p in the amygdala increased HRs’ anxiety-like behavior in the open field test and elevated plus maze. Viral-mediated miR-101a-3p over-expression also reduced expression of the histone methyltransferase Ezh2, which mediates gene silencing via tri-methylation of histone 3 at lysine 27 (H3K27me3). Knockdown of Ezh2 with short-interfering RNA (siRNA) also increased HRs’ anxiety-like behavior, but to a lesser degree than miR-101a-3p over-expression. Overall our data demonstrate that increasing miR-101a-3p expression in the amygdala increases anxiety-like behavior and that this effect is at least partially mediated via repression of Ezh2. This work adds to the growing body of evidence implicating miRNAs and epigenetic regulation as molecular mediators of anxiety behavior.

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“…Enzymatic inhibition of EZH2, the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that plays a pivotal role in catalyzing the methylation of the lysine 27 of histone H3 (H3K27), has been intensively explored as cancer therapy. Two leading compounds, EPZ-6438 and GSK126, demonstrate preliminary benefits in a small subset of hematological malignances, including diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (Kurmasheva et al, 2017;Lee et al, 2014; McCabe et al, 2012b) bearing EZH2 gene mutations. EZH2 mutations result in constitutively activated EZH2 enzymatic activity and are believed to drive a H3K27 methylation (H3K27me)dependent cell growth resembling well-defined oncogenic drivers (Brach et al, 2017;Huet et al, 2017;McCabe et al, 2012a;Morin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors

Huang

Yan

Zhang

et al. 2018

Cell

179

134

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Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. We profile global posttranslational histone modification changes across a large panel of cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1's interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.

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Initial testing (stage 1) of tazemetostat (EPZ‐6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program

Cited by 91 publications

References 41 publications

Invited Review: Dysregulation of chromatin remodellers in paediatric brain tumours – SMARCB1 and beyond

Invited Review: Dysregulation of chromatin remodellers in paediatric brain tumours – SMARCB1 and beyond

Amygdalar expression of the microRNA miR‐101a and its target Ezh2 contribute to rodent anxiety‐like behaviour

Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors

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