Delving into the Latest Updates on EZH2i(The Institute of Cancer Research) with Synapse

Overview

Basic Info

Drug Type

Degradable Molecular Glue

Synonyms-

Target

CRBN x EZH2

Action

modulators, inhibitors

Mechanism

CRBN modulators(Cereblon modulators), EZH2 inhibitors(Histone-lysine N-methyltransferase EZH2 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication

Multiple Myeloma

Inactive Indication-

Originator Organization

The Institute of Cancer Research: Royal Cancer Hospital

Active Organization

The Institute of Cancer Research: Royal Cancer Hospital

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Mongiardini, Vera ; Eccleston, Mark ; Hawkes, Cheryl ; Latarani, Maryam ; Rigas, Sushila ; Jachetti, Elena ; Mahmood, Namra ; Alborelli, Ilaria ; Colombo, Mario Paolo ; Wang, Yuzhuo ; Gangadharannambiar, Priyadarsini ; Pucci, Perla ; Fischetti, Irene ; Grimaldi, Benedetto ; Akamatsu, Shusuke ; Crea, Francesco ; Manzo, Massimiliano

BACKGROUND:

Aggressive Variant Prostate Cancers (AVPCs) are incurable malignancies. Platinum-based chemotherapies are used for the palliative treatment of AVPC. The Polycomb Repressive Complex 2 (PRC2) promotes prostate cancer progression via histone H3 Lysine 27 tri-methylation (H3K27me3). EZH2 encodes the catalytic subunit of PRC2. A recently developed nucleosome capture technology (Nu.Q^Ⓡ).measures H3K27me3 levels in biological fluids. EZH2 inhibitors (EZH2i) are being tested in clinical trials. We hypothesize that epigenetic reprogramming via EZH2i improves the efficacy of Carboplatin in AVPC and that EZH2i activity can be measured via both cellular- and cell-free nucleosomal H3K27me3 (cf-H3K27me3) levels.

METHODS:

We studied the expression of PRC2 genes in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on cellular- and cf-H3K27me3 levels. We measured dose-dependent effects of Carboplatin with/without EZH2i on AVPC cell viability (IC₅₀). We used RNA-Seq to study how EZH2i modulates gene expression in AVPC cells.

RESULTS:

PRC2 genes were significantly up-regulated in AVPC vs other prostate cancer types. EZH2i reduced both cellular and cf-H3K27me3 levels. EZH2i significantly reduced Carboplatin IC₅₀. EZH2i reduced the expression of DNA repair genes and increased the expression of p53-dependent pro-apoptotic factors.

CONCLUSIONS:

EZH2i plus Carboplatin is a promising combination treatment for AVPC.

01 Jun 2024·Heliyon

Effects of EZH2 inhibitor, trichostatin A, and 5-azacytidine combinatorial treatment on osteogenic differentiation of dental pulp stem cells

Article

Author: Hegedüs, Csaba ; Hrubi, Edit ; Imre, László

Objective:

Epigenetic mechanisms play regulatory roles in dental pulp stem cell (DPSC) differentiation. The molecules that modulate these mechanisms can be used to enhance DPSC differentiation in experimental studies and clinical applications. We investigated the combined effects of an epigenetic modulator enhancer of zeste homologue 2 inhibitor (EZH2i), trichostatin A (TSA), and 5-azacytidine (5-AZA) on the osteogenic differentiation of DPSCs.

Results:

To assess osteogenic differentiation, we measured alkaline phosphatase activity, calcium deposition, and expression of osteogenic differentiation marker genes (RUNX2, BMP2, and ALPL) after 7 or 21 days of combinatorial drug treatment in normal cell culture medium or osteo-inductive medium (OIM). No synergistic effects were observed for any possible combination of EZH2i, TSA, or 5-AZA. However, the effects of these drugs and their combinations depend on the time and culture conditions.

Discussion:

We confirmed that EZH2i and TSA have positive effects on the osteogenic differentiation of DPSCs. EZH2i activates the expression of key regulatory genes (RUNX2, BMP2, and ALPL) directly, whereas TSA interacts with signalling pathways induced by supplements in OIM to activate these genes.

27 May 2024·British journal of cancer

Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma

Article

Author: van Lohuizen, Maarten ; Pandey, Gaurav Kumar ; Badhai, Jitendra ; Hulsman, Danielle ; Landman, Nick ; Puppe, Julian ; Kopparam, Jawahar

Abstract:

Background:

More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time.

Methods:

A focused drug synergy screen consisting of 20 drugs was performed by combining EZH2 inhibition with a panel of anti-cancer compounds in mesothelioma cell lines. The compounds used are under preclinical investigation or already used in the clinic. The synergistic potential of the combinations was assessed by using the Bliss model. To validate our findings, in vivo xenograft experiments were performed.

Results:

Combining EZH2i with ATMi was found to have synergistic potential against BAP1-deficient mesothelioma in our drug screen, which was validated in clonogenicity assays. Tumour growth inhibition potential was significantly increased in BAP1-deficient xenografts. In addition, we observe lower ATM levels upon depletion of BAP1 and hypothesise that this might be mediated by E2F1.

Conclusions:

We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker.

100 Deals associated with EZH2i(The Institute of Cancer Research)

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