IBCN 2018: Inhibition of a G9a/EZH2 Network Triggers an Immune-Mediated Bladder Cancer Regression

Rotterdam, The Netherlands (UroToday.com) Jesús Paramio presented his prior work regarding the roles of G9a (EHMT2), a H3K9 methyltransferase, in human bladder cancer (BC), and explored whether a novel, reversible, potent and dual inhibitor of G9a/DNMT methyltransferase activity (CM-272) could be of benefit for the management of advanced BC.  

The expression of G9a was associated with a poor clinical outcome in BC, and is associated with resistance to immune checkpoint inhibitors. CM-272 is effective in BC cells without PIK3CA mutations and inhibits an oncogenic loop mediated by G9a and EZH2. This promotes gene expression changes causing apoptosis and immunogenic cell death. 

Using a novel immunocompetent quadruple (PtenF/F; Tp53F/F; Rb1F/F;Rbl1-/-) knockout transgenic mouse model of highly aggressive metastatic muscle-invasive BC, they showed treatment with CM-272 and CDDP results in a significant tumor and metastasis regression accompanied with an in vivo activation of endogenous antitumor immune response and immunogenic cell death. In conclusion, the expression of G9a may be a biomarker of response to immunotherapy and G9a inhibition may increase efficacy of checkpoint blockage, supporting new and promising opportunities for therapy in patients with BC.

Presented by: Jesús M Paramio, Biomedical Research Institute, Molecular Oncology Unit, CIEMAT  Avenida Complutense  Madrid, Spain

Written by: Stephen B. Williams, M.D., Associate Professor, Division of Urology, The University of Texas Medical Branch, Galveston, TX. and Ashish M. Kamat, M.D. Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 16th Annual Meeting of the International Bladder Cancer Network (IBCN) October 11-13, 2018 - the Inntel Hotels Rotterdam Centre, Rotterdam, The Netherlands