Entinostat finds a path: A new study elucidates effects of the histone deacetylase inhibitor on the immune system

Abstract

Epigenetic therapies have acquired a solid place in clinical armamentariums with the recent approval of enasidenib for isocitrate dehydrogenase 2 (IDH2)-mutated acute myeloid leukemias. This adds to previous approvals of 4 histone deacetylase (HDAC) inhibitors for T-cell lymphomas or multiple myeloma in addition to the long-approved demethylating agents for myeloid disease. But, frustratingly, solid tumor indications have not emerged despite significant efforts, including numerous clinical trials with combination therapies. One recent strategy that has emerged bears perhaps more promise: the use of HDAC inhibitors and DNA-demethylating agents to upregulate components of the immune response and thereby enhance the efficacy of immunotherapy agents, particularly the immune checkpoint blockers. In this issue of Cancer, Smith and colleagues 1 demonstrate the antitumor activity of entinostat in a murine model of ovarian cancer and indicate that efficacy requires adaptive immunity. Such a finding adds support to the ongoing combination studies with immune checkpoint blockade and suggests that this strategy could be applied in ovarian cancer.HDAC inhibitors are epigenetic agents that have been studied intensively for their ability to induce histone hyperacetylation and to upregulate the expression of genes of differentiation and cell cycle control. They do this by inhibiting the HDAC-mediated enzymatic removal of acetyl groups on chromatin, resulting in the aberrant silencing of important tumor suppressors in cancer. Entinostat follows a long history of drug development that began with butyric acid derivatives in the 1980s. Butyrates were the first agents for which histone hyperacetylation was linked with differentiation-eg, with the induction of hemoglobin synthesis in K562 erythroleukemia cells. 2 Searches for other differentiating agents led to identification of the hydroxamic acid vorinostat, and its ability to inhibit HDACs was reported in 1998. 3,4 . Romidepsin was identified for its ability target Ras; but, likewise its ability to inhibit HDACs was reported in 1998. 5-7 Clinical activity and US Food and Drug Administration approval for vorinostat in 2006 and romidepsin in 2009 triggered the development of a spate of HDAC inhibitors, most of them hydroxamic acids like vorinostat. 8 Two other hydroxamic acids gained US Food and Drug Administration approval: belinostat for peripheral T-cell lymphoma and panobinostat in combination with bortezomib and dexamethasone for multiple myeloma. A different drug class was added to the HDAC inhibitors, the benzamides, including entinostat/MS275 and mocetinostat, 9 and, later, chidamide. The first clinical trials of entinostat were reported in solid tumors, leukemias, and lymphomas in 2006 and 2007. 10,11 The enzyme targets for these are the HDAC enzymes, which are divided by structure into 4 classes: enzymes 1, 2, 3, and 8 comprise class I; enzymes 4, 5, 7, and 9 comprise class IIA; enzymes 6 and 10 comprise class IIB; and HDAC11 constitutes class IV. 12 The enzymes are struc...

Histone deacetylase inhibition in combination with MEK or BCL-2 inhibition in multiple myeloma

“…MS275 (entinostat), an HDAC1, 2, and 3 inhibitor, is actively being investigated in clinical trials for numerous tumor types. 46 Moreover, FK228 (romidepsin), which mostly inhibits HDAC1 and HDAC2, has been approved by the Food and Drug Administration for the treatment of several T-cell lymphomas.…”

Lysine Acetylation, Cancer Hallmarks and Emerging Onco-Therapeutic Opportunities

“…HDAC isoenzymes were reported to be high in malignant cells [ 109 ]. HDAC inhibitors can reactivate the expression of tumor suppressors and have emerged as one type of well-characterized epigenome-targeting agents that are capable of suppressing both histone acetylation and non-histone acetylation to resolve tumors [ 110 ], halt cancer metastasis [ 111 ], reprogram cancer cell metabolism [ 112 , 113 ], modulate the immune [ 114 ], chemo [ 115 ] and radio [ 116 ] sensitivity of cancer cells. Several HDAC inhibitors have been developed and approved by the Food and Drug Administration (FDA) for cancer treatment that represent distinct HDAC specificity.…”

Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies

“…Combination trials as described above have been using different approaches to create a more susceptible environment for checkpoint inhibitors in pMMR tumors. Entinostat, a class I-selective histone deacetylase inhibitor [78] has been shown to enhance anti-PD1 activity by downregulation of immunosuppressive cell types in vivo [79]. Entinostat has shown potential in lung cancer and melanoma.…”