There are several HDAC inhibitors under clinical development, which are grouped into different structural classes (). These include the short-chain fatty acids (phenyl butyrate and valproic acid); the hydroxamic acids (trichostatin A [TSA]; vorinostat [Zolinza®, SAHA]; panobinostat [LBH589]; PCI-24781 and belinostat [PXD101]); the cyclic tetrapeptides (romidepsin [Istodax®, FK228]); and the benzamides (entinostat [MS-275]). Valproic acid has been used as an anticonvulsant for three decades, and has only recently been recognized as an HDAC inhibitor. Other compounds, including TSA, are very active in preclinical models, but are not feasible for clinical use owing to unfavorable pharmacological behavior. Most of the currently available HDAC inhibitors exhibit varying activity against many nonsirtuin HDACs (HDAC1–11) In vitro
analysis of their potency against specific HDACs has helped to parse the effects of inhibitors on specific HDACs [12
]. However, target HDAC specificity in vivo
remains unclear as the roles of specific HDACs is still not well understood.
Two HDAC inhibitors, vorinostat and romidespin, have been approved by the US FDA for treating patients with progressive, persistent or recurrent cutaneous T-cell lymphoma (CTCL) after one or more lines of chemotherapy. Vorinostat was approved in 2006 for CTCL, including mycosis fungoides and Sézary syndrome [13
]. A Phase II trial of daily oral administration of vorinostat 400 mg in 74 patients showed an objective response in nearly 30% and relief from debilitating pruritis in 32% of the patients [15
]. Continuous daily administration was associated with improved pruritis relief (73 vs 18%), as well as greater response (31 vs 9%) compared with intermittent dosing [16
In addition to CTCL, HDAC inhibitors appear to be active in acute myeloid leukemia (AML), lymphomas and myelodysplastic syndromes (MDS). Emerging data suggest that inhibition of HDACs mediates the epigenetic gene silencing in common translocations associated with certain hematological malignancies (e.g., AML–ETO fusion protein) [17
]. In a Phase I study of 41 patients with advanced leukemia and MDS treated with vorinostat, a clinical benefit was observed in 17% of patients [18
]. These patients often have limited treatment options. Vorinostat is also being studied as a single agent in other lymphomas, multiple myeloma and solid tumor malignancies including: colon, non-small-cell lung, breast, mesothelioma, glioblastoma multiforme, prostate, head and neck, renal cell, neuroendocrine, ovarian and cervical [19
Romidepsin is a cyclic peptide that was approved in 2009 for CTCL based on two Phase II studies. Romidepsin is administered by intravenous infusion at a dose of 14 mg/m2
over 4 h on days 1, 8 and 15 of a 28-day cycle. In both studies, activity was noted, with overall response rates of 34% in 71 patients (four complete responses [CRs], 20 partial responses [PRs] and 26 stable diseases [SDs]) and 34% in 96 patients (six CRs and 27 PRs), with the median duration being 13.7 and 15 months, respectively [20
The most common adverse effects associated with HDAC inhibitors include thrombocytopenia, neutropenia, diarrhea, nausea, vomiting and fatigue. Extensive studies have been performed to determine whether HDAC inhibitors are associated with cardiac toxicities. To date, there is little conclusive evidence to determine whether some or all HDAC inhibitors cause electrocardiac changes, including QT-prolongation. Most toxicities are not class-specific and have been observed with all HDAC inhibitors, with the exception of valproic acid, where somnolence appears to be dose-limiting rather than fatigue [22
Many HDAC inhibitors have demonstrated preclinical efficacy as monotherapy or in combination with other anticancer drugs for both hematological and solid malignancies. In the clinic, however, HDAC inhibitors as single agents have proven less successful for the treatment of solid tumor malignancies. Thus, much effort has been spent evaluating rational combinations of HDAC inhibitors with other anticancer modalities in clinical trials.