Imperial College London
Portrait Picture

Professor Matthew J. Fuchter

Faculty of Natural Sciences, Department of Chemistry

Professor of Chemistry
 
 
 
//

Contact

 

+44 (0)20 7594 5815m.fuchter

 
 
//

Location

 

110DMolecular Sciences Research HubWhite City Campus

//

Summary

 

Publications

Citation

BibTex format

@article{McNeish:2022:10.1158/1535-7163.MCT-21-0743,
author = {McNeish, I and Spiliopoulou, P and Spear, S and Mirza, H and Garner, I and grundland-freile, F and Cheng, Z and Ennis, D and Iyer, N and McNamara, S and Natoli, M and Fuchter, M and Brown, R},
doi = {10.1158/1535-7163.MCT-21-0743},
journal = {Molecular Cancer Therapeutics},
pages = {522--534},
title = {Dual G9A/EZH2 inhibition stimulates anti-tumour immune response in ovarian high-grade serous carcinoma},
url = {http://dx.doi.org/10.1158/1535-7163.MCT-21-0743},
volume = {21},
year = {2022}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Ovarian high-grade serous carcinoma (HGSC) prognosis correlates directly with presence of intratumoral lymphocytes. However, cancer immunotherapy has yet to achieve meaningful survival benefit in patients with HGSC. Epigenetic silencing of immunostimulatory genes is implicated in immune evasion in HGSC and re-expression of these genes could promote tumour immune clearance. We discovered that simultaneous inhibition of the histone methyltransferases G9A and EZH2 activates the CXCL10-CXCR3 axis and increases homing of intratumoral effector lymphocytes and natural killer cells whilst suppressing tumour-promoting FoxP3+ CD4 T cells. The dual G9A/EZH2 inhibitor HKMTI-1-005 induced chromatin changes that resulted in the transcriptional activation of immunostimulatory gene networks, including the re-expression of elements of the ERV-K endogenous retroviral family. Importantly, treatment with HKMTI-1-005 improved the survival of mice bearing Trp53-/- null ID8 ovarian tumours and resulted in tumour burden reduction. These results indicate that inhibiting G9A and EZH2 in ovarian cancer alters the immune microenvironment and reduces tumour growth and therefore positions dual inhibition of G9A/EZH2 as a strategy for clinical development.
AU  - McNeish,I
AU  - Spiliopoulou,P
AU  - Spear,S
AU  - Mirza,H
AU  - Garner,I
AU  - grundland-freile,F
AU  - Cheng,Z
AU  - Ennis,D
AU  - Iyer,N
AU  - McNamara,S
AU  - Natoli,M
AU  - Fuchter,M
AU  - Brown,R
DO  - 10.1158/1535-7163.MCT-21-0743
EP  - 534
PY  - 2022///
SN  - 1535-7163
SP  - 522
TI  - Dual G9A/EZH2 inhibition stimulates anti-tumour immune response in ovarian high-grade serous carcinoma
T2  - Molecular Cancer Therapeutics
UR  - http://dx.doi.org/10.1158/1535-7163.MCT-21-0743
UR  - https://aacrjournals.org/mct/article/21/4/522/689576/Dual-G9A-EZH2-Inhibition-Stimulates-Antitumor
UR  - http://hdl.handle.net/10044/1/95162
VL  - 21
ER  -
Download