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Valemetostat Shows Superiority in Patients With DLBCL
Valemetostat has demonstrated potential efficacy in patients with diffuse large B-cell lymphoma (DLBCL) that is refractory to tazemetostat. RNA/ChIP-sequencing analysis suggest that the experimental EZH1/EZH2-inhibitor averts ectopic relocation of EZH1/2 on tumor suppressor genes mainly induced by EZH2-specific inhibition and exerts a greater anti-B cell tumor effect than currently available treatments.
A phase 2 clinical study of valemetostat is now ongoing.
“EZH2 and its close homolog EZH1 are catalytic subunits of [PRC] 2 protein complex and play a crucial role for the maintenance of transcriptional repression by tri-methylating [H3K27],” wrote lead author Toshihiro Banjo, PhD, Oncology Research Laboratories II, Daiichi Sankyo, Tokyo, Japan, and colleagues.
Hyper trimethylation of H3K27 has been associated with malignant lymphoma and myeloma progression, thus several small molecules suppressing PRC2 complex activity has been developed for hematological malignancy therapy, according to the researchers.
“Valemetostat synergized with [a] wide variety of first- and second-line drugs used in DLBCL therapy both in vitro and in vivo proposing its potential combination opportunities,” explained Dr Banjo and co-authors, who added that the method by which valemetostat controls the epigenetic landscape and inhibits malignant B-cell proliferation more effectively than selective EZH2 inhibitors remains unknown.
The researchers analyzed and compared the epigenetic impact of valemetostat and tazemetostat, and found that although both inhibitors reduced cellular global H3K27me3 levels significantly, build-up of ectopic EZH1/2 in multiple tumor suppressor gene loci with tazemetostat partially reduced H3K27me3.
“Meanwhile, valemetostat treatment evidently triggered gene expression by depleting H3K27me3 and enhancing H3K27Ac mark without inducing ectopic enrichment of EZH1/2,” Dr Banjo et al concluded.
