Inhibition of G9A and DNMT methyltransferases in bladder cancer

INDICATION: Bladder cancer

Dual inhibition of G9A and DNMT methyltransferases, in combination with cisplatin and anti-programmed cell death 1 ligand 1 (PD-L1), could help to treat bladder cancer. A tool compound that inhibited both G9A and DNMT family enzymes blocked cell cycle progression and induced apoptosis and autophagy in bladder cancer cell lines. In a mouse model of metastatic bladder cancer, combining the G9A/DNMT inhibitor and cisplatin reduced tumor and metastatic burden compared with either treatment alone, and increased infiltration of CD8+ T cells and natural killer cells in primary tumors and metastases. Addition of anti-PD-L1 decreased primary tumor and metastatic burden compared with the G9A/DNMT inhibitor and cisplatin combination at 28 days, and the treatment effect was maintained for another 28 days after the therapies were withdrawn. In primary tumor samples from cisplatin-ineligible bladder cancer patients, expression of G9A, enhancer of zeste homology 2 (EZH2), and histone methylation levels correlated with patient responsiveness to anti-PD-1 therapy. Next steps include lead optimization of the tool compound for clinical testing. ...