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.

KEYWORDS:

• Epigenetics
• peripheral T-cell lymphoma
• angioimmunoblastic T-cell lymphoma
• histone deacetylase inhibitor
• DNA methylation
• targeted therapy
• predictive biomarkers

Article highlights

• Epigenetic alterations play a significant role in hematological malignancies, in large part through changes in gene expression regulated by changes in DNA methylation and histone modifications.

• Epigenetic-modifying agents that are FDA-approved for T-cell lymphoma indications include HDAC inhibitors such as vorinostat, romidepsin, and belinostat.

• DNA demethylating agents have shown promise in T-cell neoplasms such as angioimmunoblastic T-cell lymphoma, and clinical trials are underway.

• Critical areas for future work include development of more specific and less toxic epigenetic drugs; clinical validation of rational drug combinations that include epigenetic agents; and development of epigenetic biomarkers that help guide patient and drug selection.

Declaration of interest

A Feldman receives research funding from Seattle Genetics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Supported in part by R01 CA177734 from the National Cancer Institute.