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Cancer Letters 280 (2009) 192–200
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Cancer Letters
journal homepage: www.elsevier.com/locate/canlet
Mini-review
Histone deacetylase inhibitors as anti-neoplastic agents
Nicolas Batty a, Gabriel G. Malouf b, Jean Pierre J. Issa a,*
a
b
Department of Leukemia, M. D. Anderson Cancer Center, Unit 428, 1515 Holcombe, Houston, TX 77030, USA
Department of medicine, Gustave Roussy Institute, Villejuif, France
a r t i c l e
i n f o
Article history:
Received 5 March 2009
Accepted 6 March 2009
Keywords:
Histone deacetylase inhibitors
Epigenetic therapy
Hematological malignancies
Solid tumors
Surrogate markers
Cancer
a b s t r a c t
Histone deacetylase inhibitors (HDACIs) constitute a novel class of targeted drugs that alter
the acetylation status of histones and other important cellular proteins. These agents modulate chromatin structure leading to transcriptional changes, induce pleiotropic effects on
functional pathways and activate cell death signaling in cancer cells. Anti-neoplastic activity in vitro was shown in several experimental models of cancer, but the exact mechanism
of cytotoxicity and responses are not clearly understood. Phase I/II clinical trials of various
HDACIs as single agents conducted to date have shown substantial activity in cutaneous T
cell lymphoma (CTCL), preliminary activity in Hodgkin’s disease and modest activity in
myeloid neoplasms. Responses have been rare in solid tumors. Several agents are being
tested in combination therapy clinical trials, either as chemosensitizers for cytotoxic chemotherapy or radiation therapy, or in association with DNA methylation inhibitors based
on in vitro synergy. In this review, we focus on recent basic and clinical data that highlight
the anti-neoplastic role of HDACIs.
Ó 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Histone deacetylase inhibitors (HDACIs) belong to an
emerging class of anticancer agents aimed at treating neoplasms by targeting gene expression, an approach that has
been termed epigenetic therapy [1]. Histones are proteins
around which DNA is wound to form nucleosomes, the basic unit of chromatin. Post-translational modifications of
histone tails such as acetylation and methylation affect
chromatin structure and gene expression, and are one
component of epigenetic regulation in mammalian cells
[2,3]. Epigenetics, in turn, refer to changes in gene expression that, in adult cells, are stable through mitosis. Epigenetic processes are essential for development,
differentiation and stemness. Thus, histones modifications
add information content to the primary DNA sequence.
Epigenetic deregulation of gene expression was shown
to be implicated in cancer pathogenesis [4]. One of these
epigenetic alterations is histone acetylation/deacetylation.
* Corresponding author. Tel.: +1 713 745 2260; fax: +1 713 794 4297.
E-mail address: [email protected] (J.P.J. Issa).
0304-3835/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.canlet.2009.03.013
This can occur via aberrant recruitment of histone deacetylases, for example by the fusion gene products of chromosomal translocations, or by recruitment via aberrant DNA
methylation at gene promoters. Primary alterations in histone acetylases have also been described in cancer. Histone
deacetylation in the promoters of growth regulatory genes
has been found in numerous malignancies.
The protein acetylation equilibrium is sustained in cells
by interplay of two classes of enzymes: The protein acetylases and deacetylases [5]. These enzymes modulate gene
expression by the removal or the addition of acetyl groups
to lysine residues of histones. In general, acetylation is
associated with active gene expression and deacetylation
is associated with gene silencing. Inhibition of histone
deacetylases as a therapeutic tool in cancer was arrived
at in two parallel tracks [6]. The realization that acetylation
was frequently abnormal in cancer raised interest in these
agents. Indeed, HDACIs render the chromatin conformation
less tightly packed, which leads to the recruitment of the
transcriptional machinery and to transcriptional activation. In parallel, an unbiased screen for molecules that
can differentiate cancer cells in vitro identified HDACIs as
N. Batty et al. / Cancer Letters 280 (2009) 192–200
a class of agents with substantial activity in this assay. In
leukemogenesis in particular, failure of normal differentiation could result from a failure to transcribe genes which
encode proteins that either mediate or define the mature
phenotype. For optimal transcription of these genes, histones should be in a maximally acetylated state. Therefore,
the manipulation of histone acetylation may provide a
therapeutic strategy for patients with acute myeloid leukemia (AML), as well as other hematological malignancies.
Recent data uncovered the notion that protein acetylation is a common regulatory mechanisms that is not limited to histones [7]. Thus, the term HDACI is not precise
since the substrates of the enzymes inhibited include
non-histone proteins such as P53. Indeed, acetylation of
P53 is essential for its activation [8]. The class of drugs in
question would therefore more accurately be named protein deacetylase inhibitors. In this review, we aim to describe the molecular basis of HDACIs as anti-neoplastic
agents and their clinical application in oncology.
2. Molecular basis of HDACI efficacy
Histone deacetylases (HDACs) comprise a family of 18
genes that are subdivided into four classes [3]. Classes I,
II, and IV are referred to as ‘‘classical” HDACs and are generally simultaneously targeted by most HDACIs. Early work
on the mechanism of action of HDACIs has focused on their
effects on gene transcription. As shown in Fig. 1, HDACs
catalyze the removal of acetyl groups from the chromatin
core histones. HDACs induce neutralization of the charge
on the histones which allows the phosphate backbone of
the DNA to open up and therefore facilitate the transcription of many genes, including tumor suppressor genes silenced in cancer. Moreover, acetylation of histones
facilitates destabilization of DNA–nucleosome interaction
and renders DNA more accessible to transcription factors
[2]. The effects of HDACIs on gene expression are highly
selective, leading to transcriptional activation of certain
genes such as the cyclin-dependent kinase inhibitor
p21WAF1/CIP1 but repression of others [3]. As mentioned
above, HDAC inhibition not only results in acetylation of
histones but also of transcription factors such as P53,
GATA-1 and estrogen receptor-alpha. The role of this
Ac
Ac
Ac
Ac
HDACI
H2A
H2B
H33
H
H4
++
H2A
H2B
H3
H4
HDAC
HAT
Ac
Ac
Ac
Ac
Fig. 1. Schematic illustration of HDACI mechanism of action. Shown is a
schematic illustration of mechanisms by which histone deacetylase
inhibitors (HDACI), histone deacetylases (HDAC) and histone acetyltransferases (HAT) modulate gene expression. HATs catalyze the addition of
acetyl groups to lysine residues of histone tails, contributing to an open
and accessible chromatin structure. HDACs remove these groups, resulting in a closed structure, and HDACIs reverse this effect.
193
non-histone protein acetylation in in vitro and clinical responses to HDACIs remains to be clarified.
There is substantial interest in the interactions between
histone deacetylation and DNA methylation in the proximity of gene promoters [9,10]. DNA methylation attracts the
binding of HDACs to gene promoters thus promoting localized deacetylation [11]. HDACs are also components of the
Polycomb group silencing pathway active in stem cells,
and this silencing has been shown to promote DNA methylation in cancer [12], suggesting that the level of histone
acetylation can directly influence the degree of methylation of a promoter in cancer. On the other hand, HDACIs
alone rarely activate the expression of genes silenced by
promoter CpG island methylation [13], though they show
strong schedule dependent synergy with DNA methylation
inhibitors in this regard (with a requirement for demethylation to precede HDACI).
In parallel to effects on gene expression and differentiation, HDACIs have also been shown to be efficient inducers of apoptosis in several cellular systems [14]. The
precise mechanisms of this effect are under investigation,
with suggestions ranging from effects on cellular networks
to oxidative stress induction and to DNA damage induction
[15]. For example, using microarray analysis, it was demonstrated that HDACIs induces the expression of the thioredoxin-binding protein-2 (TBP-2) gene in LNCaP prostate
cells [16]. Induction of TBP-2 followed by decreased levels
of thioredoxin (TRX) was proposed to play a critical role in
SAHA-induced growth arrest and/or apoptosis in transformed cells. Separately, effects of HDACIs on the molecular chaperone heat shock protein 90 (Hsp90) may also
mediate apoptosis. SAHA was shown to induce acetylation
and inhibition of HSP90, and thus depleted the levels of
hsp90 [17]. Another HDACI Panobinostat induced hsp90
acetylation and DNA methyltransferase 1 (DNMT1) degradation [18]. These effects on hsp90 may be involved in the
observed synergy between HDACIs and many anti-neoplastic agents [14].
3. HDACIs in the clinic
Several HDACIs have shown impressive antitumor
activity in vitro with remarkably little toxicity in preclinical studies, suggesting selectivity for neoplastic cells. This
has prompted development of additional compounds,
many of which have entered phase 1 trials in various
malignancies. There are different chemical classes of HDACIs, as summarized in Table 1. Two early lead compounds,
suberoylamilide hydroxamic acid (SAHA) and pyroxamide
bear structural similarity with trichostatin A, a potent
inhibitor of HDAC. The hydroxamic acid-based hybrid polar compounds inhibit HDAC at considerably lower concentrations than those considered being cytotoxic. In recent
years, an increasing number of structurally diverse HDACIs
have been identified that inhibit proliferation and induce
differentiation and/or apoptosis of tumor cells in culture
and in animal models. The major HDACI structural classes
are hydroxamic acid: SAHA (Merck & co), CRA-024781
(Celera Genomics), LBH589 (Novartis), PXD101 (CuraGen,
TopoTarget), NVP-LAQ824 (Novartis), ITF2357 (Italfarmaco), SB939 (SBIO Pte Ltd), R306465 (Johnson & Johnson);
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N. Batty et al. / Cancer Letters 280 (2009) 192–200
Table 1
Histone deacetylase inhibitors.
Structural class Compound
Isotype
selectivity
Hydroxamic
acid
TSA
Vorinostat/Zolinza (SAHA)
I, II
I, IIa, IIb, IV
LAQ824
Panobinostat/LBH589
CRA-024781 (PCI 24781)
Belinostat/PXD101
ITF2357
SB939
R306465 (JNJ-16241199)
I, II
I, IIa, IIb, IV
I, IIb
I, IIa, IIb, IV
I, II
Unknown
I
Short-chain
fatty acids
Sodium butyrate
Valproic acid
AN-9
OSU-HDAC42
I, IIa
I, IIa
Benzamides
SNDX-275/entinostat
(MS-275)
MGCD0103
Pimelic diphenylamide
1, 2, 3, 9
II
1, 2, 3, 11
1, 2, 3
II
1, 2, 4, 6
II
Cyclic peptides Romidepsin/
depsipeptide (FK 228)
Apicidin
HC-toxin
Thiolate
Nonhydroxamic
acid
Carboxamides
Oxadiazoles
NCH-51
Alpha-mercaptoketone 19y
(KD5150)
Study
phase
FDA
approval
(CTCL)
I
II
I
II
II
I
I
I
II
I, II
Pan-HDACI
and higher CTCL who had failed two systemic therapies
(one of which must have contained bexarotene). In this
study population, the overall response rate was 30% with
median response duration of 168 days [24].
Vorinostat was evaluated in other hematological malignancies, with a response seen in Hodgkin’s disease [22]. A
phase I study of vorinostat in patients with leukemias was
recently reported [25]. Forty one patients were included,
31 of whom had acute myeloid leukemia (AML). The
remaining patients had other leukemias or myelodysplastic syndrome. The subjects received 100–300 mg doses of
oral vorinostat two or three times daily for 14 days, followed by 1 week of rest. The maximum tolerated dose
(MTD) was 250 mg three times daily. Five patients (12%)
had adverse experiences that required dose reduction.
Twenty-nine patients dropped out of the study because
of disease progression. Seven patients (17%) achieved a
complete response (CR), a complete response with incomplete blood count recovery, or hematological improvements; all had AML. All of these patients received
vorinostat doses at or below the recommended level.
Vorinostat has been also examined as a single agent in
various phase I and phase II studies. In the setting of refractory disease, vorinostat was found to have modest to no
activity in myeloma, head and neck cancer, breast cancer,
thyroid cancer and other malignancies [26–31].
3.2. Depsipeptide
5-(Trifluoroacetyl)thiophene-2- 4, 6
carboxamides
2-Trifluoroacetylthiophene
II
oxadiazoles
CTCL, cutaneous T-cell lymphoma; HDAC, histone deacetylase; Class I:
HDAC 1, 2, 3, 8; class IIa: HDAC 4, 5, 7, 9; class IIb HDAC 1, 2, 3, 8; class IIb:
HDAC 6, 10; class IV: HDAC 11.
short-chain fatty acids: valproic acid, benzamides: MS-275
(Syndax), MGCD0103 (MethylGene), cyclic peptides:
FK228 (Gloucester), thiolate, non-hydroxamic acid, carboxamides, oxadiazoles.
The next set of milestones for this field was to define
the optimal profile of HDAC isoform targets by comparing
the pan-HDACI hydroxamic acid with other selective HDACIs. A novel HDACI has been developed recently to target
HDAC6 [19]. In fact, HDAC6 is a new class II enzyme which
seems to play a role in metastasis, in deacetylation of
Hsp90, and in the regulation of apoptosis [20,18]. We describe next the main HDACIs in phase I/II clinical trials.
3.1. Vorinostat
Vorinostat (suberoylamilide hydroxamic acid, (SAHA),
(Zolinza, Merck & Co., Inc.) is a hydroxamic acid that is a
pan-HDACI. Vorinostat was approved by the U.S. Food
and Drug Administration, for the treatment of Cutaneous
T-Cell Lymphoma (CTCL) [21]. This was based on promising data in a phase I study [22], which led to a phase II
study in which 33 patients with CTCL were enrolled that
produced an overall response rate of 31% at a vorinostat
dose of 400 mg [23]. Another major trial supporting vorinostat approval was a single-arm open-label phase IIB
multicenter trial that enrolled 74 patients with stage IB
Romidepsin/depsipeptide [32] (FK 228) Gloucester
Pharmaceuticals (Cambridge, Massachusetts, USA) is a cyclic peptide that selectively inhibits HDAC isotypes 1, 2, 4
and 6. Phase I studies of depsipeptide yielded several different dose schedules that were evaluated in phase II studies. A common schedule is 17.8 mg/m2 on day-1 and -5
every 21 days [33]. In that schedule, dose-limiting toxicities were fatigue, nausea, vomiting, and transient thrombocytopenia
and
neutropenia.
In
depsipeptide
monotherapy trials, complete responses were reported in
CTCL [34] and in AML [35]. A multicenter phase II study
of depsipeptide in CTCL is ongoing. Just like vorinostat,
minimal efficacy was observed in other malignancies,
including lung cancer, renal cancer, colon cancer, CLL and
other malignancies [36,33,37–40]. In the lung cancer trial,
translational studies did show global gene expression
changes after depsipeptide, and it was suggested that the
drug could be evaluated further as a biological response
modifier [37]. A controversy has arisen over the safety of
depsipeptide. Some studies have raised concerns about observed EKG changes and possible cardiac toxicity [41], but
a careful review suggested that some of the cardiac events
observed were related to established risk factors [42]. Nevertheless, the fact that vorinostat, depsipeptide and another potent HDACI panobinostat all cause EKG changes
have raised the issue of a class effect on cardiac toxicity
for HDACIs.
3.3. Valproic acid
Valproic acid is a short-chain fatty acid that is a weak
HDAC inhibitor [43]. Its long term availability as an anti-
N. Batty et al. / Cancer Letters 280 (2009) 192–200
seizure drug prompted its evaluation in oncology as an epigenetic acting drug. A single agent study demonstrated
minor responses in patients with the myelodysplastic syndrome (MDS) [44]. Most of the clinical data on valproic
acid has come from combination studies, discussed below.
3.4. Other HDACIs
Several HDACIs are in ongoing clinical trials, though
clinical data so far has not suggested major differences between the different drugs. Belinostat, a potent HDACI
in vitro has completed phase I evaluation and entered
phase II studies [45,46]. The early data in heavily pre-treated patients has shown stable disease in a fraction of patients, with no major responses. Panobinostat is one of
the most potent HDACIs in vitro. Following phase I studies,
ongoing studies are evaluating it in CTCL and Hodgkin’s
disease with preliminary evidence of activity [47].
MGCD0103, an oral HDACI entered clinical trials with the
goal of testing the potential benefits of an isotype-selective
inhibitor. Phase I studies showed the typical side-effects of
HDACIs [48,49], with rare responses in heavily pre-treated
patients. A phase II study reported promising activity in
refractory Hodgkin’s disease [50]. Other studies are summarized in Table 2.
4. Combination studies
4.1. Combinations with DNA methylation inhibitors
As discussed earlier, there is strong, schedule dependent synergy between DNA methylation inhibitors and
HDACIs at the level of gene expression regulation. This
has prompted several studies of combining these two classes of agents in hematological malignancies, and this concept is now being tested in solid tumors as well. Completed
phase I/II studies include decitabine + valproic acid [51],
azacitidine + valproic acid + retinoic acid (ATRA) [52] and
azacitidine + MS275 [53]. All these studies demonstrated
safety of the combinations, and response rates that were
encouraging though not definitively superior to single
agent DNA methylation inhibitors. A common finding in
these studies was relatively rapid time to response, and it
was suggested that this may be a surrogate sign for synergy. Those studies also found increased toxicity with the
combinations, particularly neurotoxicity (confusion, somnolence) and fatigue, which are common side-effects of
HDACIs. These combinations are now being tested in randomized studies in patients with MDS and AML. In parallel,
valproic acid combination with azacitidine has also been
tested in patients with advanced solid tumors [54]. These
studies are too early to comment on efficacy, though
encouraging results have been reported.
4.2. Other combinations
Presumably through effects on apoptosis [15], HDACIs
have been found to be synergistic with many different
therapies including cytotoxics, targeted therapies and radiation therapy. These combinations are slowly making their
way to the clinic. Examples of ‘‘promising” combinations
195
include valproic acid with epirubicin [55], vorinostat with
idarubicin [56], vorinostat with carboplatin and paclitaxel
[57] (responses in 11/25 patients with non-small cell lung
cancer), etc. Table 2 lists additional recent trials of HDACI
combinations in solid tumors. Some of these have already
led to randomized studies, which may introduce HDACIs
into the mainstream of anti-neoplastic therapy for common diseases.
5. Research issues
Several aspects of epigenetic therapy pose significant
clinical and translational challenges. In particular, while
HDACIs are considered targeted agents, this approach is
conceivably non-specific due to the numerous downstream effects on gene expression. Thus, translational research will be essential to clarify the precise mechanisms
of in vivo action (and resistance) of the drugs.
5.1. In vivo mechanisms of action
A fascinating aspect of the clinical data so far is the
selectivity of HDACIs (as single agents) for some lymphoid
malignancies such as CTCL and Hodgkin’s disease. The
mechanism of this selectivity is mysterious, and, if elucidated, may well prove to be very useful to advance this
therapy towards treatment of other malignancies. Data reported so far include preferential induction of apoptosis in
CTCL cell lines in vitro [58], expression of HDAC2 in aggressive CTCL [59], gene expression modulation in vivo [47],
and a gene expression signature predictive of response in
leukemias [25] (in a small number of patients). None of
these studies clearly explain the selectivity of HDACIs for
CTCL, and a careful evaluation of this issue is one of the
most pressing research questions in the field.
5.2. Surrogate assays
Since HDACIs cause accumulation of acetylated histones
in tumors and in normal tissues, an assay for the accumulation of acetylated histones might be useful as an intermediary marker of HDAC inhibition and especially to be
incorporated into future clinical trials as a surrogate end
point for analysis. The assessment of histone H3 and H4
acetylation in peripheral blood mononuclear cells has been
the most frequently used molecular model in HDACI pharmacodynamic studies [60]. However, the modulation of histone acetylation has not predicted clinical responses so far
and has not been used to guide dose selection. An assay of
HDAC enzymatic activity in intact cells using a cell-permeant substrate with a fluorescent read-out was tested in
two phase I trials of MGCD0103 [2,49]. It is not clear whether
this is superior to measuring histone acetylation directly.
There are no reported attempts to measure non-histone protein acetylation in patients treated with HDACIs so far.
5.3. Differences between the HDACI drugs
The proliferation of HDACI leads to the natural question
of differences between them. Reported differences include
potency, isotype selectivity, administration route and
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N. Batty et al. / Cancer Letters 280 (2009) 192–200
Table 2
Recent HDACI studies in solid tumors.
HDACI
Dose
Phase
Other
Therapy
Disease
N
Response
Reference
SAHA
400 mg/day
I
BelCaP
9
Four had PR (1 head & neck cancer,
3 NSCLC) & 2 had SD
[68]
SAHA
I/II
Bevacizumab
8
3/7. One pt with mixed response
had SD for >18 months. Two pts SD
for 5 and 6 months
[69]
II
Tamoxifen
Breast cancer
19
Four patients (1 CR, 3 PR: 4/17,
24%)
[70]
SAHA
200 mg orally twice
daily 14 days, and bevacizumab
15 mg/kg intravenously every
21 days
400 mg daily for three of four
weeks and tamoxifen 20 mg daily,
continuously
200 mg bid 14 days q 3 weeks
Advanced
solid
malignancies
Renal cell
cancer
68
Five of the first 22 patients (23%)
were progression-free at 6 months
[71]
SAHA
400 mg daily in 21-day cycles
II
23
(mg/kg/day): 15, 30, 45, 60, 75, 90,
100, 120, 140 and 160
I/II
44Phase I
3/9 response-evaluable pts
achieved SD
OR in the phase I part 9/41 (22%);
SD/minor response in 16/41 (39%).
[72]
VPA
Recurrent
glioblastoma
multiforme
HRPC, s/p
chemotherapy
Locally
advanced or
metastatic
breast cancer
10Phase
II
42
In the breast-specific phase II part,
PR-4/8 (50%) and SD-2/8 (25%),
progression in 1/8 (12.5%)
PR 7/37 (19%)
SAHA
II
FEC100
FEC100 (600/100/600 mg/m2)
VPA
IV loading (mg/kg) + epirubicin
(mg/m2): 15/75, 30/75, 45/75, 60/
75, 75/75 and 75/100, oral loading:
75/100, 90/100, 100/100, 120/100,
140/100 and 160/100
I
Epirubicin
Advanced
solid tumors
MGCD0103
50 mg, 75 mg, and
90 mg + Gemcitabine
I
Gemcitabine
Refractory
solid tumors
21
MGCD0103
50 mg, 75 mg, and
90 mg + Gemcitabine
I/II
Gemcitabine
Refractory
solid tumors
25 in
phase I
and 4
in
phase
II
SD 16/37 (43%)
1 PR occurred in a patient with
pancreatic cancer and 7/21 pts
were assessed as stable disease
after 2 cycles
14 response-evaluable phase I pts,
2/5 PR in pancreatic Cancer
[73]
[73]
[74]
[75]
MGCD0103
Five dose levels have been
evaluated (mg/m2): 12.5, 20, 27, 36,
and 45
I
Advanced
solid tumors
28
Two unconfirmed PR
2/14 SD
3/7 renal cancer, 1/8 colon cancer
Depsipeptide
13 mg/m2 intravenously over 4 h on
days 1, 8, and 15 of a 28-day cycle
II
25
2/25(8%)
[77]
Depsipeptide
1, 2, 3.3, 5, 7, 9 mg/m2
I
Refractory or
metastatic
renal cell
cancer
Thyroid and
other
advanced
cancers
19
11-SD
[78]
Depsipeptide
4 h infusion followed by
gemcitabine over 30 min on days 1,
8, and 15 of a 28 day cycle initial
romidepsin/gemcitabine dose level
was 10/800 mg/m2
13 mg/m(2) as a 4-h iv infusion on
days 1, 8, and 15 of a 28-day cycle
I
Pancreatic
and other
advanced
solid tumors
33
[79]
Previously
treated CRC
patients with
advanced
disease
25
One patient with ovarian cancer
experienced a minor response
(29%) and 12 pts SD for > 4 cycles (5
pancreatic, 4 breast, 1 NHL, 1
ovarian, 1 ampullary cancer)
No Objective response
Depsipeptide
II
Gemcitabine
[76]
[80]
(continued on next page)
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N. Batty et al. / Cancer Letters 280 (2009) 192–200
Table 2 (continued)
HDACI
Dose
Phase
Belinostat
1000 mg/m2/day was administered iv on days 1–5 of a 21 day
cycle
II
Other
Therapy
Disease
N
Response
Reference
Platinum resistant
EOC and LMP
ovarian tumors
18 EOC
EOC: 9/18
SD
[81]
12
LMP
Belinostat
BelCaP (Bel 1000 mg/m2 5 days; carboplatin AUC 5 1 day
3; paclitaxel 175 mg/m2 1 day 3) was given in 3 week cycles
II
Pivanex,
AN-9
2.34 g/m2/day was administered as a 6-h continuous
intravenous infusion, daily for 3 days, and repeated every
21 days until disease progression
II
CI-994
Paclitaxel 225 mg/m2 over 3 h and carboplatin AUC = 6 on day
1; CI-994 or matching placebo capsules 4 mg/m2/day on days
1–7 of each cycle and 5 mg/m2 daily during the EP
II
R306565
Four dose levels (100, 200, 300 and 400 mg)
MS-275
3 mg MS-275 biweekly (days 1 + 15 of a 4-week cycle) or 7 mg
MS-275 weekly (days 1 + 8 + 15 of a 4-week cycle)
BelCaP
Relapsed EOC.
35
Advanced NSCLC
47
NSCLC
182
I
Solid tumors or
lymphoma
15
II
Metastatic
melanoma
14 + 14
BelCaP
LMP: 9/12
SD
1/12 PR
10/35 PR
(31%)
16/35-SD
1/47 PR
14/47-SD
67 pts
(37%)
entered
the EP
4 pt SD for
4 months
4/14 for
3 mg group
3/14 for
7 mg group
[82]
[83]
[84]
[85]
[86]
BelCaP Carboplatin and Paclitaxel; CRC colorectal cancer; EOC epithelial ovarian cancer; EP Blinded Extension Phase; FEC100 5-fluorouracil, epirubicin and
cyclophosphamide; GBM glioblastoma multiforme; HRPC Hormone refractory prostate cancer, LMP micropapillay/borderline ovarian; tumors; NSCLC nonsmall cell lung cancer; OR Objective response; Pivanex, AN-9 Pivaloyloxymethyl butyrate; Pts patients; RCC renal cell cancer; SD stable disease; VPA
Valproic acid.
spectrum of side-effects. Whether these are clinically relevant to efficacy, remains to be determined. It is striking
that every HDACI tested in CTCL so far has shown substantial efficacy, suggesting a shared mechanism of action despite in vitro differences.
5.4. Toxicity
HDACIs have been largely well tolerated with a reasonable toxicity profile. An interesting group of side-effects
has emerged as a common feature of HDACIs in the clinic,
suggesting a class effect. The mechanisms underlying this
class effect are not known. The most common adverse effects to many HDACIs were fatigue and weakness [61].
Gastrointestinal toxicity including diarrhea resulting in
electrolyte disturbances is common but mild and tolerable
in most patients. Neurocortical manifestations were reported primarily with phenylbutyrate and valproic acid.
Cardiac side-effects such as non-specific EKG changes were
reported in phase I trials of romidepsin while sudden cardiac death reported in the phase II trials although other
risk factors for sudden death were present in those patients [42]. Prolonged QT interval has also been demonstrated in both intravenous and oral vorinostat
formulations [62] and in a dose dependant fashion with
intravenous panobinostat [63]. Thrombocytopenia has
been dose limiting in some studies but is usually mild
and transient. Anemia and neutropenia were infrequent,
and septic complications were rare.
5.5. Mechanisms of resistance
The initial and acquired resistance to HDACIs [25]
may explain some of their limited benefit. A number of
studies demonstrated several pathways that are involved
in the biology of resistance and sensitivity to HDACIs and
vorinostat in particular. In a transgenic mouse model of
B-cell lymphoma, the overexpression of the antiapoptotic
proteins Bcl-2 or Bcl-XL or deletion of the proapoptotic
BH3-only proteins Bim and Bid was shown to convey
resistance to vorinostat therapy [64]. Another study
using a functional genetic screen found that the ectopic
expression of two genes, RAR-alpha and PRAME, a
repressor of RA signaling can cause resistance to growth
arrest and apoptosis induced by HDACI of different
chemical classes [65]. Recently, an HDACI resistant
HL60 cell line clone was reported to be lacking HDAC6
expression [66]. There have been very few studies on
in vivo mechanisms of HDACI resistance. In one such
study, using immunohistochemical analysis of STAT1
and phosphorylated tyrosine STAT3 (pSTAT3) in skin
biopsies obtained from CTCL patients, it was demonstrated that nuclear accumulation of STAT1 and high levels of nuclear pSTAT3 in malignant T cells correlates with
a lack of clinical response [67]. This suggested that constitutive activation of signal transducers and activators of
transcription predicts vorinostat resistance in CTCL.
Clearly more such studies are needed to guide the next
generation of clinical trials.
198
N. Batty et al. / Cancer Letters 280 (2009) 192–200
6. Conclusions
The use of HDACIs allows the potential switching on or
off of genes deregulated in cancer. These drugs also have
other effects on neoplastic cells, including through acetylation of non-histone proteins. Clinically, promising results
have been observed in lymphoid neoplasms but, as monotherapy, efficacy has been limited in other malignancies.
Nonetheless, novel combinations of HDACIs with DNA
methylation inhibitors or with cytotoxic therapy may lead
to augmented antitumor activity. Many questions have
been raised by this relatively non-specific therapy: Precise
mechanisms of in vivo activity or resistance, mechanisms
of class-effect toxicities, minimally effective dose and predictive markers for response. An understanding of the
HDACIs multisystemic effects [15] will provide better insights to advance the field through defining appropriate
dosages, minimizing untoward effects and investigating
HDACIs for a broad range of indications.
Conflict of Interest
None of the authors has any financial and personal relationships with other people or organisations that could
inappropriately influence (bias) their work.
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