Recent Advances in the Targeting of Epigenetic Regulators in B-Cell Non-Hodgkin Lymphoma

Abstract

In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field.

Mantle cell lymphoma management trends and novel agents: where are we going?

“…DNA hypomethylating agents such as 5-azacytidine or decitabine have shown limited activity and are toxic in MCL and other B-cell lymphomas. 76 However, cladribine, but not fludarabine, is a cryptic hypomethylating agent that inhibits DNA, RNA, and histone methylation by inhibiting s-adenosyl methionine (SAM), the donor of methyl groups. 77 In MCL, cladribine has been shown to have activity as a single agent that is synergistic with rituximab.…”

Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy

“…BET inhibitors (BETi) have gained increasing attention in recent years as potent modulators of genes involved in disease progression across several cancers [ 189 ]. BRD4 is the most studied BET protein in the context of therapeutic targets.…”

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

“…The reversible nature of epigenetic modifications makes them a strategic tool in the treatment of many disorders and pathological states. Several epigenetic drugs targeting the activity of DNA methyltransferases as 5-azacytidine or 5-aza-2 -deoxycytidine and histone deacetylases (Suberoylanilide hydroxamic acid, Panobinostat, Belinostat, Romidepsin) have been approved by FDA (the U.S. Food and Drug Administration) for anticancer therapy and many others, especially affecting the histone methylation status, are at the clinical testing stage, including inhibitors of DOT1L methyltransferase (Pinometostat), EZH2 methyltransferase (Tazemtostat, GSK-126 or 3-Deazaneplanocin A), JMJD3 demethylase (GSK-J1, GSK-J4), and LSD1 (GSK-2879552, INCB059872 or INCB057643) [48,150,151].…”