The Use of Histone Deacetylase Inhibitors for the Treatment of Solid Tumors

US Oncological Disease, 2007;1(2):12-6

‘Epigenetics’ is a term used to describe heritable states of gene expression that are not due to changes in DNA sequence. Epigenetic phenomena have been shown to play an important role in carcinogenesis and tumor progression. Such phenomena also represent potential therapeutic targets for cancer treatment as they are potentially reversible. Two such phenomena are epigenetic changes in DNA methylation, resulting in altered genetic expression, and histone modifications.1 This article focuses on histone modifications and thebalance of acetylation/deacetylation in tumor cells as a therapeutic target for anticancer therapies.

Background
DNA wraps around a core of eight histone proteins (pairs of H2A, H2B, H3, and H4) to form nucleosomes. Lysine residues on histones are a target of acetylation, via histone acetyltransferases (HATs), and deacetylation, via histone deacetylases (HDACs). Acetylation neutralizes the positive charge of the lysine ε-amino group of the core histone tail. Put simply, this results in an ‘unwrapped’ DNA conformation, allowing access to DNA by transcription factors and co-activators. Deacetylation of lysine residues leads to tighter packaging of DNA and silencing of transcription.1

Mutations in HATs and recruitment of HDACs have both been associated with transcriptional repression of genes, resulting in cell growth and neoplastic transformation.2 These enzymes also have non-histone substrates, including transcription factors and other proteins, and the balance of acetylation/deacetylation can influence protein stability, protein localization, binding of transcription factors to DNA, and apoptosis. There are four classes of HDAC, with class I, II, and IV HDACs possessing a catalytic domain with a zinc pocket, which is important for the binding of HDAC inhibitors (HDACi). Zinc-independent and nicotinamide adenine dinucleotide (NAD)-dependent class III HDACs are not affected by the HDACi currently in clinical development. Class I HDACs are found mainly in the nucleus, while class II HDACs (4, 5, 6, 7, 9, and 10) are seen in both the nucleus and the cytoplasm.3,4 The class IV family consists of HDAC11, which shares features of both class I and class II enzymes.4 Several classes of HDACi have been identified (see Table 1):5,6
  • short-chain fatty acids, such as phenylbutyrates;7
  • hydroxamic acids, including trichostatin A (TSA);8
  • vorinostat (suberoylanilide hydroxamic acid (SAHA)),9 oxamflatin, belinostat (PXD101), LAQ824, and LBH589;
  • cyclic tetrapeptides containing a 2-amino-8-oxo-9, 10-epoxy-decanoyl (AOE) moiety, trapoxin A;10
  • cyclic peptides not containing the AOE moiety, romidepsin (depsipeptide, FK228), and apicidin;11 and
  • benzamides, including MS-275 (SNDX-275) and MGCD0103.12
This article focuses on HDACi in the treatment of solid tumors. Since the only US Food and Drug Administration (FDA)-approved HDACi to date is vorinostat, which was approved for use in cutaneous T-cell lymphoma (CTCL),the data leading to its approval are also presented here. Otherwise, the focus is on research in solid tumors; information on trials examining HDACi in hematological malignancies, including lymphoma, is not included. This article is not designed to discuss each HDACi in detail, but to present an overview of the available clinical data on HDACi, focusing on phase II trials.

Phase II Data for Single-agent Histone Deacetylase Inhibitors

Vorinostat

To date, vorinostat is the only HDACi approved by the FDA for the treatment of malignancy. It is an orally active and potent inhibitor of HDAC activity,inhibiting both class I (HDAC1, HDAC2, HDAC3) and class II (HDAC 6) HDACs at nanomolar concentrations. It was approved in October 2006 for the treatment of cutaneous manifestations of CTCL in patients with progressive, persistent, or recurrent disease, or following two systemic therapies (www.fda.gov/cder/Offices/OODP/whatsnew/vorinostat.htm). This approval was based on the results of two open-label clinical trials. The pivotal study supporting FDA approval was an open-label trial that enrolled 74 patients with stage IB–IVA CTCL who had received at least two prior systemic therapies. Patients were treated with 400mg oral vorinostat daily until disease progression or intolerable toxicity resulted. The primary end-point of the study was objective response rate (ORR), with secondary end-points of time to response (TTR), time to progression (TTP), duration of response (DOR), and relief of pruritis. ORR was 29.7%, with median DOR not reached but estimated to be ≥185 days; median TTP was 4.9 months, and 32% of patients reported relief of pruritis. The most common drug-related adverse events were diarrhea, fatigue, nausea, and anorexia, but ≥grade 3 events included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea (4%).13

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