Clinical development of histone deacetylase inhibitors






Margarita SALCEDO MAGGUILLI, PhD
Oncology Research and Development Unit
Servier International Research
Institute (IRIS)

Clinical development of histone deacetylase inhibitors


by M. Salcedo Magguilli, France



The genome exists naturally in a repressed state. Most of the DNA is occluded by nucleosomes assembled into highly condensed structures inaccessible to regulatory and functional proteins required for gene transcription initiation. Transient opening of chromatin regions is driven by chromatin remodeling factors and histone-acetyltransferases (HAT) associated with the polymerase complex. HAT action is reversed by histone deacetylases (HDAC). HDAC expression is modified in many tumors and their overexpression has been correlated with poor clinical outcome in certain cancers. In the past few years, HDAC inhibitors (HDACi) have been extensively studied as antitumor drugs. The HDACi vorinostat and romidepsine are approved in the US for the treatment of cutaneous T-cell lymphoma. Romidepsine has been approved for the treatment of peripheral T-cell lymphoma and belinostat is currently under priority review at the US Food and Drug Administration for the same indication. Vorinostat has also been registered in Japan. Therapeutic benefit of HDACi as monotherapy in solid tumors has not yet been demonstrated. Multiple clinical trials are currently under way to evaluate these agents alone or in combination with other antitumor strategies in hematological and solid tumors. However, better understanding of the pleiotropic antitumor effects of these molecules, as well as the identification of accurate predictive biomarkers, is still required to further develop these drugs in the future.

Medicographia. 2014;36:300-310 (see French abstract on page 310)



The major part of the genome exists as nucleosomes comprising ≈146 bp of DNA coiled 1.7 times around an octamer of histone proteins (H2A, H2B, H3, and H4 histones; two of each). Nucleosome stability is maintained by multiple contacts along the entire length of the nucleosomal DNA. The histone N-terminal tails protrude from the nucleosome particle, allowing availability of these sites for histone modifications that regulate the structure and function of chromatin. The genome is, by default, in a repressed state due to these highly condensed and inaccessible nucleosome structures.

Depending on stimuli received by the cell during cell differentiation, a concerted action of sets of transcription factors specific to each cell type and to their state of differentiation and activation, drives gene expression and thus protein synthesis. This becomes possible via the chromatin structure regulation driven by remodeling factors and histone-acetyltransferases (HAT) associated with the polymerase complex, which is reversed by histone deacetylase (HDAC) recruited to chromatin that has just been transcribed. This chromatin regulation mediated by the HAT and the HDAC, together with DNA methylation, constitute the major mechanisms of functionally relevant genome changes not linked to nucleotide sequence alterations, called epigenetics.1

Many disease stages have been found to involve epigenetic deregulation. Diseases of blood cells have constituted an invaluable field of investigation that has allowed a better understanding of epigenetic failures, leading to aberrant growth and differentiation and, ultimately, to malignant development. They have also provided insight into autoimmune or inflammatory diseases where the immune system is chronically active.

The main types of drugs that have been developed to target epigenetic deregulation in recent years are molecules interfering with methylation and acetylation enzymes. Even though reversible histone acetylation was discovered in 1964,2 it was only until 1996 that the first bona fide histone deacetylase, HDAC1, was isolated and cloned.3 Since then, structure and function of HDAC have been widely explored, and HDACi started to be developed and studied to treat a variety of conditions, such as neurological disorders, immune disorders, hematological diseases, HIV and other viral, bacterial, and parasite infections, graft vs host disease, and mainly cancer.4

Although inhibition of HDAC would be expected to result in a global increase in gene transcription, only 20% of all known genes are affected by HDACi. About 10% of them are down regulated and the others are upregulated.5 It is now clear that HDACi antitumor activity is not limited to inhibition of histone deacetylation by HDACi, but also to inhibition of HDAC-mediated deacetylation of other proteins. This HDACi action leads to interference with HDAC-concerted regulation and interaction with transcription factors, signal-transduction molecules, DNA-repair proteins, chaperone proteins, and corepressors. The result of these HDACi pleiotropic effects is a multitude of antitumor activities, with exquisite tumor specificity. However, mechanisms and specificity of these activities are not fully understood. Indeed, HDAC isotype function does not seem to be redundant and differs depending on cell types.6





The latest efforts in HDACi development have focused on the design of molecules with improved HDAC specificity and pharmacokinetic profile, hoping to reduce their toxicity and increase their therapeutic benefit. Preclinical and clinical studies combining HDACi with other anticancer drugs have multiplied in the recent years. Whether these improvements will have an impact on clinical effect remains to be demonstrated. This review will attempt to give an overview of current HDACi clinical development strategies, as well as unsolved questions and future directions in this field.


Figure 1
Figure 1. Chemical reaction for lysine acetylation and deacetyation.

(A) The classical family of histone deacetylase (HDAC) removes the acetyl group
from acetyl lysine, releasing acetate and the reaction requires zinc (Zn+), while
(B) Sirtuins remove the acetyl group using a completely different mechanism,
releasing products that are different from acetate in a nicotinamide adenine
dinucleotide (NAD+)–dependent reaction.
Abbreviations: ADP, adenosine diphosphate; HAT, histone-acetyltransferases.


HDAC family

HDAC are a family of enzymes found in numerous organisms, including bacteria, fungi, plants, and animals, that catalyze the removal of acetyl groups from ε-N-acetylated lysine residues of various proteins substrates, including histones, transcription factors, α-tubulin, and nuclear importers.7 In humans, 18 HDAC genes have been identified. Eleven of these HDAC contain highly conserved deacetylase domains and are zinc (Zn+)- dependent enzymes, while seven are nicotinamide adenine dinucleotide (NAD+)–dependent proteases with additional adenosine diphosphate-ribosyltransferase and other enzymatic activities (Figure 1). Based on sequence phylogeny and their homology to yeast HDAC, their subcellular localization, and enzymatic activity, they are divided as follows.8

Zn+-dependent HDAC
Class I (HDAC1, 2, 3, and 8). These HDAC are homologous to the yeast Rpd3 protein, mainly found in the nucleus, although HDAC8 is also found in the cytoplasm or associated to the cell membrane. Their main targets are histones. They are small and expressed ubiquitously. Knockout animal studies have shown that they are involved in cell survival, proliferation, and differentiation.

Class II (HDAC4, 5, 6, 7, 9, and 10). These HDAC are homologous to the yeast Hda1 protein, are large, act in association with tissue specific transcription factors, and have both histone and nonhistone protein targets. They have a more tissue-specific regulatory function than class I HDAC. Class II HDAC are further divided in two subclasses: class IIa (HDAC4, 5, 7, and 9) and class IIb (HDAC6 and 10). They are expressed in a limited number of cell types, and either shuttle between the nucleus and cytoplasm (ie, class IIa), or are mainly cytoplasmic (ie, class IIb).

Class IV (HDAC11). This HDAC shares sequence similarity with the catalytic core regions of both class I and II enzymes, but does not have a strong enough sequence identity to be placed in their class.

NAD+-dependent HDAC
Class III, also called sirtuins (SIRT). There are seven human SIRTs (SIRT1 to 7) and they are homologous to the yeast protein Sir2. They regulate gene expression in response to changes in the cellular redox status, cell proliferation, differentiation, genome stability, cell survival, metabolism, energy homeostasis, organ development, aging, and cancer. SIRT1, 2, 3, 5, 6, and 7 have lysine deacetylase activity while SIRT4 and 6 display monoribosyltransferase activity. SIRT5 has also been shown to have protein lysine demalonylase and desuccinylase activities. They shuttle between the nucleus and the cytoplasm.9

HDAC inhibitors

In 1977, Riggs and colleagues described the induction of acetylated histone accumulation upon exposure to n-butyrate,10 and soon after, Candido and colleagues published that n-butyrate inhibited deacetylation.11 However, specificity of this inhibition was not fully demonstrated. In 1987, trichostatin A (TSA), isolated from a Streptomyces strain as an antifungal compound, was described as an inducer of murine erythroleukemia cell differentiation agent12 and three years later, its action as a HDACi was demonstrated.13 TSA has a hydroxamic acid group that can chelate a metal ion. Later on, trapoxin, a fungal cyclic peptide that had been identified as an inducer of morphological change in transformed cells, was also found to inhibit HDAC by a mechanism involving its epoxyketone moiety and its ability to strongly bind to HDAC.14 Indeed, trapoxin was used to isolate HDAC1 for the first time.3

In 1998, two HDACi that later became clinically relevant were reported: suberoylanalide hydroxamic acid (SAHA, vorinostat) and FK228 (romidepsin). Vorinostat was designed and synthesized as a hybrid polar compound that strongly induced erythroid differentiation,15 whereas romidepsin is an antitumor cyclic depsipeptide isolated from Chromobacterium violaceum.16


Figure 2
Figure 2. Pharmacophore model for zinc (Zn+)-dependent histone deacetylase
inhibitors (HDACi).

A common model generally accepted for the HDACi is depicted in this figure. All molecules
share a zinc-binding moiety (ZBG) in the catalytic pocket, a capping group (Cap), and a
straight-chain alkyl, vinyl, or aryl linker connecting the two parts (hydrophoboic linker). A kink
atom (connecting unit, CU) connects the linker to the Cap.
After reference 17: Giannini G et al. Future Med Chem. 2012;4:1439-1460. © Futurescience.



Zn+-dependent HDACi may come from natural or synthetic sources. Examples of natural sources include Chromobacterium violaceum (depsipeptide), sponge association between Poecillastra sp and Jaspis sp (Psammaplin A), Streptomyces (TSA), dietary fibers (butyric acid), garlic (Diallyl disulfide), and cruciferous vegetables such as broccoli (Sulphorophane). Synthetic and natural HDACi have a common pharmacophoric model characterized by a zinc-binding moiety in the catalytic pocket, a capping group, and a straight-chain alkyl, vinyl, or aryl linker connecting the two parts. A kink atom (connecting unit) connects the linker to the capping group (Figure 2).17

They can be classified according to their chemical structure into the following groups: (i) carboxic acids; (ii) benzamide derivatives; (iii) cyclic tetrapeptides (epoxyketones and nonepoxyketones); (iv) hydroxamic acids; (v) ketones; and (vi) miscellaneous structures.

NAD+-dependent HDACi target either their substrate-binding cleft or the NAD+-binding domain according to docking studies.9 They may be classified according to their chemical structure as follows8: (i) NAD derivatives; (ii) naphtopyranone inhibitors; (iii) dihydrocoumarin derivatives; and (iv) 2-hydroxynaphtaldehyde derivatives.

Based on in vitro biochemical assays using purified HDAC isoenzymes, HDACi such as vorinostat, panobinostat, belinostat, or abexinostat have been identified as pan-HDACi, since they inhibit both class I and class II HDAC. Other inhibitors are more selective towards class I HDAC, eg, mocetinostat, entinostat, and romidepsin. More limited is the number of HDACi with selective inhibition of class II HDAC.17-19 However, the true significance and clinical impact of these specificities remain to be well characterized. Biochemical screening used to determine HDAC specificity does not reflect physiological conditions, since they act in general in macromolecular complexes. Therefore, there is a strong need for developing cellbased screening assays to determine HDACi specificity and their biological effect in a cell dynamic context.

Antitumor effect of HDACi

Rather little is known today about the antitumor effects of NAD+-dependent HDACi. SIRT1 is the HDAC of this family that has been most studied in human epithelial, neuronal, hematopoietic, and mesenchymal malignancies. In addition, SIRT1 has been described to be involved in both tumor promotion and tumor suppression activities.9 In a recent clinical trial, the pan-sirtuin inhibitor niacinamide was reported to improve clinical outcome when combined with vorinostat in germinal center-derived diffuse large B-cell lymphoma (DLBCL).20 However, these inhibitors are neither potent enough nor specific enough. Their effect on cancer remains unclear.

In contrast to NAD+-dependent HDACi,Zn+-dependent HDACi have been widely studied. The most fascinating and attractive feature of HDACi as antitumor agents is the resistance of normal cells to the action of these molecules. In contrast, inhibition of the pleiotropic effects of HDAC in tumor cells mediates their death by numerous mechanisms, as described in preclinical and clinical studies.21,22 This effect is mostly related to the regulation of gene expression as a consequence of changes in the level of acetylation of histone and nonhistone proteins. However, the contribution of a single mechanism to therapeutic effect is likely to depend on the specific cancer cell type and the specific genetic perturbations in that tumor.23 The main antitumor effects of Zn+-dependent HDACi are briefly discussed below.

Apoptosis
HDACi have been described to regulate the expression of both proapoptotic and antiapoptotic genes. This regulation results in the activation of both extrinsic and intrinsic apoptotic pathways shifting the balance away from cell survival and toward cell death. Downregulation of prosurvival proteins such as BCL-2, BCL-XL, MCL-1, FLIP, and X-linked inhibitor of apoptosis protein (XIAP) have been described in different models.24-28 They have also been shown to upregulate proapoptotic proteins, such as BIM, BAK, NOXA, BMF, and BAX, by acetylation and stabilization of specific promoters or p53 protein.29-33 Death receptors and ligands that mediate extrinsic pathway apoptosis are upregulated upon treatment with HDACi. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) sensitivity may be restored in TRAIL-resistant malignant cells.34

In addition, BH3 interacting domain death agonist (BID), the only member of the BCL-2 family that is primarily activated through the extrinsic apoptotic pathway, has been shown to be activated after cell exposure to HDACi, leading to cell death.35-37

Angiogenesis
HDAC inhibition has been found to negatively regulate hypoxia- inducible factor (HIF)–1α, which mediates the expression of several genes involved in angiogenesis via the increased expression of vascular endothelial growth factor (VEGF).38 HDACi decrease endothelial nitric oxide synthase (eNOS), enhance expression of antiangiogenic molecules thrombospondin- 1 and activin-A, and downregulate proangiogenic basic fibroblast growth factor (FGF).39,40

Induction of oxidative injury
Generation of reactive oxygen species (ROS) in transformed cells exposed to HDACi has long been recognized35 and its toxicity has been attributed to induction of thioredoxin.41 Administration of antioxidants has been shown to diminish HDACi effect, while conversely, interference with antioxidant defenses increases sensitivity to HDACi in some models.42 DNA damage induction associated with HDAC inhibition has been attributed to ROS generation.43

Interference with DNA repair
HDACi have been shown to trigger early double-stranded DNA breaks in cancer cells probably associated with ROS generation44 measured by the induction of phosphorylated histone H2AX.45 Furthermore, HDACi may disrupt DNA repair by favoring acetylation of DNA repair proteins and/or downregulating them. Examples of these HDACi-targeted proteins are Ku70, Ku 86, RAD50, RAD51, BRCA1, and MRE11.30,46-48 Interestingly, disruption of DNA repair by HDACi may be more pronounced in transformed vs normal cells, contributing to their selectivity.49,50

Interference with checkpoint regulation
HDACi can act at multiple points in the cell cycle progression at different phases of the cell cycle to block progression, notably in G1, G2, and mitosis. Each cell-phase block is associated with a different outcome. HDACi block progression from G1 into S phase by upregulating genes that negatively control this process, notably CDK inhibitor p21. This can deliver a cytostatic effect that is reversed with the removal of the drug, and is seen on both normal and tumor cells.51 HDACi also induce G2/M arrest by downregulation of G2/M phase specific cyclins,52 however, this results in cell protection from HDACi. The HDACi-sensitive G2 phase arrest is defective in the majority of immortalized, virally transformed, or tumor cell lines. In these cells, HDACi treatment leads to aberrant mitosis by several mechanisms that can trigger cell death, and therefore represents a selective cytotoxicity in comparison with normal cells, which are protected by a normal G2 phase arrest.53,54

Other effects
Other HDACi-mediated mechanisms that contribute to their antitumor effect comprise: (i) proteotoxic and endoplasmic reticulum stress through disruption of aggresome and accumulation of misfolded proteins55; (ii) interference with the function of corepressors such as Bcl-6, a corepressor involved in lymphomagenesis56; (iii) interference with signaling pathways by regulation of protein kinases including mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), glycogen synthase kinase (GSK)-3β, p38, and STAT-557-60; (iv) proteasome inhibition and alteration of the expression of the ubiquitinated-protein shuttle HR23B61-62; (v) interruption of cytoprotective autophagy63; (vi) repression of metastasis-related genes64; (vii) immune regulation either by inhibiting inflammation mediators65 or by inducing immune responses against tumors66; (viii) interference with chaperone function, in particular hyperacetylation of Hsp90, reducing its association with cancer-related proteins, which results in their proteosomal degradation67; and (ix) elimination of cancer stem cells (CSC).

Late clinical development and approval of HDACi

The hydroxamic acid vorinostat (SAHA, Zolinza® from Merck Sharp & Dohme Corporation) and the cyclic peptide romidepsine (FK228/depsipeptide, Istodax® from Celgene) are approved in the US for the treatment of relapsed cutaneous T-cell lymphoma (CTCL). Romidepsine obtained fast-track approval for the treatment of peripheral T-cell lymphoma (PTCL) and the hydroxamic acid belinostat (PXD101, Beleodaq® from Topotarget/ Spectrum Pharmaceuticals) is currently under priority review at the US Food and Drug Administration (FDA) for the same indication.

In addition, the Merck licencee, Taiho, has registered vorinostat for the treatment of CTCL in Japan. The benzamide chidamide is an HDAC10 inhibitor (Epidaza® from Shenzhen Chipscreen Bioscience) that has been submitted for registration in China for the treatment of PTCL, and has been licenced to Huya bioscience in the US.

Vorinostat was approved in 2006 by the FDA on the basis of two phase 2 studies: one pivotal and one supportive. In the pivotal study, 74 patients with CTCL at stage 2B or higher were treated in an open-label, single-arm study. Response was assessed by the severity-weighted assessment tool (SWAT), and it was concluded that 30.5% of the patients had clinically important pruritus relief and 13.6% had complete resolution of their pruritus. This effect was maintained for at least 4 weeks. The main observed adverse events were nausea, diarrhea, thrombocytopenia, and anemia.70,71 However, the European Medicines Agency (EMA) considered that the clinical benefit was not compelling and was lacking overall survival assessment. In addition, reported responses were considered by the agency as partial responses. As a consequence, Merck withdrew its European marketing application in 2009 (EMEA/ 90664/2009).

Romidepsin was approved in 2009 by the FDA on the basis of two open-label, single-arm trials. The overall response rate of CTCL patients was similar in both studies (34% and 35%) based on investigator assessments. Serious adverse events included infections, arrhythmia, edema, leukopenia, and thrombocytopenia.72 In 2011, the FDA granted accelerated approval for this drug for the treatment of PTCL on the basis of a phase 2 single-arm trial, where objective response rate (ORR) was 25%, including 15% complete response. The median response was 17 months. Adverse events in these patients included thrombocytopenia, neutropenia, and infections.73 In 2012, the EMA confirmed the refusal of the approval of this drug due to a lack of an established benefit as a result of a noncomparative nature of the pivotal efficacy data submitted (EMA/CHMP/27767/2013).

A summary of currently registered phase 3 studies is shown in Table I.74,75

HDACi in early clinical development

More than 390 clinical trials using HDACi are registered at the National Institutes of Health clinical trials registry.75 Most of them study the therapeutic action of HDACi in cancer indications. Of interest, the pan-HDACi abexinostat have shown promising durable responses in early clinical trials in lymphoma patients (ORR 30%). In particular, follicular lymphoma patients have shown an ORR of 46%. Evaluable patients who achieved objective responses included 3 complete responses and 13 partial responses. The safety profile was manageable. Enrollment in the phase 2 part of the study of this investigational HDACi drug is currently ongoing (personal communication).

The development of new generation HDACi has focussed on designing molecules with better pharmacokinetic profiles and/ or better potency, and/or narrower HDAC target specificity. In addition, several novel HDACi have been molecularly designed as hybrid molecules in order to either concomitantly inhibit another tumor-related target such as PI3K and topoisomerase I, or to promote tumor-specific localization.18,76 An interesting exercise of HDACi-related toxicity improvement has been pioneered by the group developing abexinostat. An administration schedule has been conceived on the basis of pharmacokinetic/pharmacodynamic modeling to diminish the thrombocytopenia toxic effect of this HDACi. This schedule has been successfully applied to patients.77,78

Given the relatively restricted spectrum of activity of HDACi when administered as single agents, the development of combination therapies has multiplied. Numerous closed or ongoing trials study the effect of various HDACi in combination with standard cytotoxic agents based on the hypothesis that HDACi would lower the survival threshold of tumor cells.22,50,79-80 In addition, potentiation of antitumor efficacy by combining HDACi with radiotherapy has been shown in preclinical studies81-83 and has been well tolerated in metastatic patients.84


Table I
Table I. Histone deacetylase inhibitors (HDACi) in phase 2/3 or phase 3 clinical trials.

Abbreviations: AML, acute myeloid leukemia; CTCL, cutaneous T-cell lymphoma; DNMTi, DNA methyl transferase inhibitor; EFS, event-free survival; EORTC, European Organisation for Research and Treatment of Cancer; HCT, hematopoietic cell transplantation; ORR, objective response rate; OS, overall survival; MM, multiple myeloma; NCI, National Cancer Institute; PFS, progression-free survival; NSCLC, non–small cell lung cancer.
After references 74 and 75: Citeline, Pharmaprojects. https://servier-pipeline.citeline.com/CpAccount.aspx; US National Institutes of Health. www.clinicaltrials.gov.



Combination of HDACi with targeted therapies has also been widely explored. Considerable evidence has shown that proteasome inhibitors act synergistically with HDACi.85-88 In the absence of normal proteasome function, misfolded proteins are degraded via formation of aggresome, and this pathway depends on HDAC6. When HDAC6 is inhibited, aggresomes cannot function, and this results in proteotoxic-induced apoptosis. Indeed, several clinical trials have shown encouraging results in multiple myeloma when combining the proteasome inhibitor bortezomib with romidepsin,89 vorinostat,90 and panobinostat.91 Another therapeutic combination studied in clinical trials is the synergy observed with inhibitors of DNA methyl transferase (DNMT), which enhances reactivation of tumor suppressor genes. Notably two studies combining vorinostat or belinostat with DNMT inhibitors (DNMTi) indicated that the combination may result in clinical efficacy and showed that the treatment was well tolerated in patients with myeloid malignancies.92,93 Multiple other combination approaches have been explored in preclinical studies based on scientificallybased synergistic combinations or counteraction of HDACiresistance mechanisms, and which have started to translate in clinical settings.19,94,95 These include combinations with agents targeting several tyrosine kinases,67,96-103 Hsp90,97,104 apoptotic proteins,26,33,34,103,105-107 CDKs,108 NF-κβ,109 autophagy,110 or the immune system.66,111,112

A summary of HDACi in early clinical phases is given in Table II (page 306).74,75


Table II
Table II. Histone deacetylase inhibitors (HDACi) in early clinical trials.

Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; API, aminopeptidase inhibitor; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; cMPN, chronic myeloproliferative neoplasms; CRC, colorectal cancer; CT, chemotherapy; CTCL, cutaneous T-cell lymphoma; DNMTi, DNA methyl transferase inhibitor; DLBCL, diffuse large B-cell lymphoma; HoT, hormone therapy; HCC, hepatocellular carcinoma; HL, Hodgkin’s lymphoma; IM, immunomodulators; MDS, myelodisplastic syndrome; MM, multiple myeloma; NHL, non-Hodgkin’s lymphoma; NSCLC, Non–small cell lung cancer; PI, proteome inhibitor; RT, radiotherapy; TKI, tyrosine kinase inhibitor.
After references 74 and 75: Citeline, Pharmaprojects. https://servier-pipeline.citeline.com/CpAccount.aspx; US National Institutes of Health. www.clinicaltrials.gov.


Pending questions and future directions

Despite the fact that HDACi represent attractive antitumor drugs due to a minimal effect on normal tissuees and relatively low toxicity, clinical evidence of efficacy remains limited, in particular in solid tumors.113

The clinical impact of the improvement introduced in new generation HDACi and/or of various combination therapy strategies is not yet well established. None of them are approved yet, nor adopted as therapeutic options. However, it is hoped that continued translational research efforts will enable better identification of resistant vs susceptible patient populations. For example, ZFP64, a member of the C2H2 type zinc-finger family, has been identified as a possible predictive biomarker of response to the HDACi resminostat of patients with hepatocellular carcinoma, as published in the 4SC product web site information.114 Predictive biomarkers of response to HDACi include STAT1 and high phosphorylation of STAT3 in B- and T-cell lymphoma cell lines,58 and genes involved in antioxidation,115 as well as HR23B in CTCL patients treated with vorinostat.61 Nevertheless, a recent study in malignant pleural mesothelioma cell lines showed that this marker did not predict vorinostat sensitivity in vitro,116 indicating that efforts to find relevant predictive biomarkers taking into account tumor types should continue.

A more recent approach to improve understanding of how HDACi could be developed and used more effectively is the use of cell-based screening assays. These assays are anticipated to better reflect physiological conditions in which HDACi exert their antitumor activity, ie, in concert with other proteins that impinge on gene transcription. In addition, they could allow a better grasp of mechanisms by which, in certain conditions, HDACi may actually promote tumor growth and metastasis.117

Continued monitoring of efficacy in ongoing clinical studies linked to the application of pertinent translational research approaches are anticipated to lead to the identification of smarter clinical strategies, in terms of sensitive patient selection, HDAC tumor type specificity, and combination strategies in the near future. ■

Acknowledgments: I thank Jean-Pierre Abastado, Ioana Kloos, and Michael Burbridge for critical reading of this article as well as Isabelle Sanson, Anne Trincot, and Stephanie Lemen for technical assistance.


Keywords: cancer; clinical trial; epigenetics; gene expression; HDAC; HDAC inhibitor; histone deacetylase





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