EPIGENETIC VULNERABILITIES: PRE-CLINICAL AND CLINICAL EVIDENCES

Abstract

Epigenetic therapy has been an active area of investigation since epigenetic dysregulation has been shown to be involved in the pathogenesis of hematological malignancies. Inhibitors of histone deacetylases (HDACi) were the first being recognized as a potentially effective treatment approach for lymphoma and entered clinical practice in cutaneous and peripheral T-cell lymphomas with three FDA approved compounds. In mature lymphoid malignancies, single agent trials of agents who proved beneficial in myeloid malignancies such as inhibitors of DNA methyltransferases (DNMTi), bromodomain and extra-terminal domain proteins (BETi) or isocitrate dehydrogenases (IDHi) have been disappointing. Overall, In B-cell lymphoma, the initial enthusiasm has been tempered by the limited efficacy in monotherapy or the suboptimal benefit-risk ratio compared to other emerging therapeutic classes, notably bispecific antibodies and CARTs. This research has found a second wind with the design of new agents targeting enhancer of zeste homologue 2 (EZH2) in follicular lymphoma, EZH1–2 in ATLL/PTCL, protein arginine N-methyltransferases (PRMTs), mainly PRMT5 in Hodgkin and T-cell lymphoma and even BCL6, a master gene involved in B-cell lymphoma through perturbation of BCL6-regulated epigenetic programs

This review highlights the most recent findings with these agents and promising future directions of research in this area including their potential in overcoming epigenetically driven drug resistance mechanisms, in combination with chemotherapy especially when biomarker driven or with new immunotherapies in view of their ability to modify the tumor microenvironment.

Keywords: genomics, epigenomics, and other -omics

No potential sources of conflict of interest.