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Targeting epigenetic regulators in the treatment of T-cell lymphoma.

ABSTRACT: Introduction: T-cell lymphomas represent a broad group of malignant T-cell neoplasms with marked molecular, clinical, and biologic heterogeneity. Survival rates after conventional chemotherapy regimens are poor for most subtypes and new therapies are needed. Rapidly expanding knowledge in the field of epigenomics and the development of an increasing number of epigenetic-modifying agents have created new opportunities for epigenetic therapies for patients with this complex group of diseases.Areas covered: The present review summarizes current knowledge on epigenetic alterations in T-cell lymphomas, availability, and mechanisms of action of epigenetic-modifying agents, results of clinical trials of epigenetic therapies in T-cell lymphomas, status of FDA approval, and biomarker approaches to guide therapy. Promising future directions are discussed.Expert opinion: Mutations in epigenetic-modifying genes are among the most common genetic alterations in T-cell lymphomas, highlighting the potential for epigenetic therapies to improve management of this group of diseases. Single-agent efficacy is well documented, leading to FDA approval for several indications, but overall response rates and durability of responses remain modest. Critical next steps for the field include optimizing combination therapies that incorporate epigenetic-modifying agents and developing predictive biomarkers that help guide patient and drug selection.

SUBMITTER: Ahmed N

PROVIDER: S-EPMC7110907 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Targeting epigenetic regulators in the treatment of T-cell lymphoma.

Ahmed Nada N Feldman Andrew L AL

Expert review of hematology 20200122 2

<b>Introduction</b>: T-cell lymphomas represent a broad group of malignant T-cell neoplasms with marked molecular, clinical, and biologic heterogeneity. Survival rates after conventional chemotherapy regimens are poor for most subtypes and new therapies are needed. Rapidly expanding knowledge in the field of epigenomics and the development of an increasing number of epigenetic-modifying agents have created new opportunities for epigenetic therapies for patients with this complex group of disease ...[more]

PMID: 31903826

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Project description:Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of clinically aggressive diseases associated with poor prognosis. Except for ALK + anaplastic large-cell lymphoma (ALCL), most peripheral T-cell lymphomas are highly malignant and have an aggressive disease course and poor clinical outcomes, with a poor remission rate and frequent relapse after first-line treatment. Aberrant epigenetic alterations play an important role in the pathogenesis and development of specific types of peripheral T-cell lymphoma, including the regulation of the expression of genes and signal transduction. The most common epigenetic alterations are DNA methylation and histone modification. Histone modification alters the level of gene expression by regulating the acetylation status of lysine residues on the promoter surrounding histones, often leading to the silencing of tumour suppressor genes or the overexpression of proto-oncogenes in lymphoma. DNA methylation refers to CpG islands, generally leading to tumour suppressor gene transcriptional silencing. Genetic studies have also shown that some recurrent mutations in genes involved in the epigenetic machinery, including TET2, IDH2-R172, DNMT3A, RHOA, CD28, IDH2, TET2, MLL2, KMT2A, KDM6A, CREBBP, and EP300, have been observed in cases of PTCL. The aberrant expression of miRNAs has also gradually become a diagnostic biomarker. These provide a reasonable molecular mechanism for epigenetic modifying drugs in the treatment of PTCL. As epigenetic drugs implicated in lymphoma have been continually reported in recent years, many new ideas for the diagnosis, treatment, and prognosis of PTCL originate from epigenetics in recent years. Novel epigenetic-targeted drugs have shown good tolerance and therapeutic effects in the treatment of peripheral T-cell lymphoma as monotherapy or combination therapy. NCCN Clinical Practice Guidelines also recommended epigenetic drugs for PTCL subtypes as second-line therapy. Epigenetic mechanisms provide new directions and therapeutic strategies for the research and treatment of peripheral T-cell lymphoma. Therefore, this paper mainly reviews the epigenetic changes in the pathogenesis of peripheral T-cell lymphoma and the advancement of epigenetic-targeted drugs in the treatment of peripheral T-cell lymphoma (PTCL).

Project description:Rationale: Constitutive activation of the NF-κB signalling pathway plays a pivotal role in the pathogenesis of activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCLs), the most aggressive and chemoresistant form of DLBCL. In ABC-DLBCLs, the CARMA1-BCL10 (CB) complex forms a filamentous structure and functions as a supramolecular organizing centre (CB-SMOC) that is required for constitutive NF-κB activation, making it an attractive drug target for ABC-DLBCL treatment. However, a pharmaceutical approach targeting CB-SMOC has been lacking. Here, we developed Bcl10 peptide inhibitors (BPIs) that specifically target the BCL10 filamentation process. Methods: Electron microscopy and immunofluorescence imaging were used to visualize the effect of the BPIs on the BCL10 filamentation process. The cytotoxicity of the tested BPIs was evaluated in DLBCL cell lines according to cell proliferation assays. Different in vitro experiments (pharmacokinetics, immunoprecipitation, western blotting, annexin V and PI staining) were conducted to determine the functional mechanisms of the BPIs. The in vivo therapeutic effect of the BPIs was examined in different xenograft DLBCL mouse models. Finally, Ki67 and TUNEL staining and histopathology analysis were used to evaluate the antineoplastic mechanisms and systemic toxicity of the BPIs. Results: We showed that these BPIs can effectively disrupt the BCL10 filamentation process, destabilize BCL10 and suppress NF-κB signalling in ABC-DLBCL cells. By examining a panel of DLBCL cell lines, we found that these BPIs selectively repressed the growth of CB-SMOC-dependent DLBCL cells by inducing apoptosis and cell cycle arrest. Moreover, by converting the BPIs to acquire a D-retro inverso (DRI) configuration, we developed DRI-BPIs with significantly improved intracellular stability and unimpaired BPI activity. These DRI-BPIs selectively repressed the growth of CB-SMOC-dependent DLBCL tumors in mouse xenograft models without eliciting discernible adverse effects. Conclusion: We developed novel BPIs to target the BCL10 filamentation process and demonstrated that targeting BCL10 by BPIs is a potentially safe and effective pharmaceutical approach for the treatment of ABC-DLBCL and other CB-SMOC-dependent malignancies.

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Targeting epigenetic regulators in the treatment of T-cell lymphoma.

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Targeting epigenetic regulators in the treatment of T-cell lymphoma.

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