Promising antitumor activity with MGCD0103, a novel isotype-selective ...

Drug Evaluation

1.

Introduction

2.

Rationale for targeting histone deacetylases

3.

MGCD0103

4.

Conclusions

5.

Expert opinion

Promising antitumor activity with MGCD0103, a novel isotype-selective histone deacetylase inhibitor Christophe Le Tourneau & Lillian L Siu† University of Toronto, University Health Network, Princess Margaret Hospital, Division of Medical Oncology and Hematology, Toronto, Canada

Background: Histone deacetylases (HDACs), which target histones as well as non-histone proteins as substrates, have the potential to regulate aberrant gene expression and restore normal growth control in malignancies. Objective: This review provides an updated summary of preclinical and clinical experience with the oral isotype-selective HDAC inhibitor MGCD0103 in cancer. Methods: Data presented in abstract form from international conferences or journal articles found within a PubMed search of article up to May 2008 are described in this review. Results/conclusions: MGCD0103 appears tolerable and exhibits favorable pharmacokinetic and pharmacodynamic profiles with evidence of target inhibition in surrogate tissues. Clinical and pharmacodynamic data support a three-times-weekly administration at a 90-mg fixed dose. MGCD0103 displays promising antitumor activity in hematological and lymphoproliferative diseases. Keywords: cancer, HDAC inhibitor, Hodgkin’s lymphoma, isotype selectivity, pharmacodynamic, pharmacokinetic Expert Opin. Investig. Drugs (2008) 17(8):1247-1254

1.

Introduction

Epigenetic changes that occur through the modulation of chromatin structure have been implicated in carcinogenesis and malignant transformation [1]. The basic repeating unit of chromatin is the nucleosome, consisting of DNA wrapped around a histone octamer [2]. Histone hyperacetylation promotes chromatin relaxation and is associated with gene transcription, while histone hypoacetylation promotes chromatin condensation and is associated with gene silencing [3]. Chromatin modulation and its associated effects on gene expression are controlled by the opposite actions of two families of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria [4]. They have been intensively scrutinized over the past decade because deregulation of HDAC activity has been found in many human cancers [5]. In addition, decreased levels of histone acetylation have been observed in some solid tumors, such as breast, prostate and liver cancer, and correlated with clinical outcome [1,6-8]. These findings have led to the clinical development of HDAC inhibitors (HDACi) in cancer therapy. Interestingly, the use of HDACi predated the discovery of HDACs themselves. In fact, the inhibitors have been used for the purification and cloning of mammalian HDACs. MGCD0103 is an orally available, isotype-selective HDACi that is currently being evaluated for its anticancer activity, as a single agent and in combination with chemotherapy. We review here the preclinical data as well as the clinical 10.1517/13543780802256896 © 2008 Informa UK Ltd ISSN 1354-3784 All rights reserved: reproduction in whole or in part not permitted

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MGCD0103

development of MGCD0103, and highlight the specificities of this compound in comparison to the first generation of less specific HDACi. 2. Rationale for targeting histone deacetylases 2.1

Histone deacetylation in normal cells Histone deacetylase biological activity

2.1.1

Human HDACs have been classified into four classes, based on their homology to yeast HDACs [4]. Classes I, II and IV HDACs share a zinc-dependent catalytic domain with a high degree of homology among the classes, while class III HDACs have a unique catalytic mechanism that requires the cofactor nicotinamide adenine dinucleotide (NAD). In mammals, class I HDACs (HDAC1, HDAC2, HDAC3 and HDAC8) are related to the yeast-reduced potassium dependency 3 (RPD3) HDAC. Class II HDACs (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10) are related to the yeast histone deacetylase 1 (HDA1), and have a more complex domain organization. Class III HDACs, also called sirtuins, have homology to yeast silencing information regulator 2 (SIR2). HDAC11 is the unique member of class IV HDACs and has conserved residues in its catalytic centre that are shared by both class I and II HDACs. HDACs are found in all fully sequenced free-living eukaryotic organisms, except class IV HDACs that are not found in fungi. 2.1.2

Histone deacetylase substrates

It is thought that HDACs evolved in the absence of histone proteins [4]. Indeed, phylogenetic analysis of bacterial HDACs indicates that the evolution of these enzymes preceded the evolution of histones, suggesting that their primary targets may not be histones [9]. In fact, the function of the so-called ‘HDACs’ is to remove acetyl groups from lysine residues on proteins, and may have therefore been more properly referred to as ‘lysine deacetylases’ [10]. Furthermore, HDAC substrates are not only histones but also non-histone proteins, such as p53, c-Myc, ER-α, Rb, STAT3, HSP90, α-tubulin, amongst others, and non-protein molecules. Nonetheless, histones are by far the most abundant HDAC substrates, and histone acetylation represents a key target for the action of most HDACs. The conservation of these proteins indicates that each HDAC class might have a unique and non-redundant role in basic cell biological processes. Histone deacetylase inhibitiors as anticancer agents Mechanisms of action of histone deacetylase inhibitors

these genes [12]. This broad spectrum has led some authors to hypothesize that HDAC inhibition may not be specific enough to display antitumor activity. The expression of different classes of genes can be altered by HDACi; amongst them, the tumor suppressor gene p21 is one of the most commonly induced [13]. These gene expression changes ultimately can result in the inhibition of proliferation, induction of apoptosis, cell cycle arrest, and differentiation in cancer cells [10]. HDACi have also been shown to block angiogenesis by inhibition of hypoxia-inducible factors [14]. In contrast, normal cells are almost always considerably more resistant to HDACi than tumor cells, thus providing a therapeutic index for this class of agents as potential anticancer compounds [15]. 2.2.2

Structural classes of histone deacetylase inhibitors

To date, an increasing number of structurally diverse HDACi have emerged for clinical development [11]. They can be divided into various chemical classes including hydroxamic acid derivatives, cyclic peptides, aliphatic acids, and benzamides. All except the benzamides target part or all of class I and II HDACs, whereas benzamides such as MGCD0103 and MS-275 are deemed isotype-selective as they avoid the class II HDACs [16]. At least 14 different HDACi are undergoing clinical trial evaluations as monotherapy or in combination with chemotherapy or radiation therapy. The available results of these clinical trials have recently been reviewed elsewhere [11]. Vorinostat, a hydroxamic acid derivative, is the first HDACi to be approved by the US FDA for clinical use in the treatment of cutaneous T-cell lymphoma [17]. Interestingly, HDACi also seem to have potential therapeutic application in non-malignant diseases, including neurodegenerative diseases associated with memory impairment [18], sickle-cell anemia [19], and HIV infection [20]. 3.

MGCD0103

3.1

Chemical name, structure and properties

MGCD0103 is a chemically synthesized, orally available, isotype-selective small-molecule HDACi, highly specific for classes I and IV HDACs, with negligible inhibitory activity (median inhibitory concentration IC50 > 10 µM) against class II HDACs (Table 1). The chemical name of MGCD0103 is N-(2-Amino-phenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)methyl] benzamide dihydrobromide (Figure 1). The molecular weight of MGCD0103 is 558.27 g/mol.

2.2

Preclinical data

2.2.1

3.2

The mechanisms of action of HDACi are complex and not completely elucidated [11]. The anticancer activity of HDACi is thought to be achieved by restoring aberrant gene expression at the transcriptional level in cancer cells. Up to 20% of all expressed genes are affected by HDACi, probably including both direct and downstream effects on the transcription of

MGCD0103 has been shown to have potent and selective antiproliferative activity at submicromolar concentrations against human cancer cells from various origins, but not against normal human cells, in vitro [21]. Consistent with its antiproliferative activity, MGCD0103 induced at low µmolar concentrations significant dose-dependent cell cycle arrest and apoptosis of human cancer cells [21]. It also strongly

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Expert Opin. Investig. Drugs (2008) 17(8)

Le Tourneau & Siu

Table 1. IC50s of MGCD0103 against recombinant human histone deacetylases. HDAC enzyme

IC50 (µM)

1

0.15

2

0.29

3

1.66

4

> 10

5

> 10

6

> 10

7

> 10

8

> 10

11

0.59

N

N

N H

NH2 H N

N

3.3.2

O

⋅2HBr

Figure 1. Chemical structure of MGCD0103.

upregulates transcription of the p21 gene in a dose-dependent manner, regardless of p53 status in HCT116, A549, p53-null T24 and U937 cell lines [21]. From in vivo studies, MGCD0103 had significant antitumor activity at well-tolerated doses against a broad spectrum of human cancer types, such as colon (HCT116, SW48 and Colo205), non-small-cell lung (A549), prostate (DU145), pancreatic (PANC1) and vulval epidermal (A431) cancer models [21]. At the tested MGCD0103 dose of 90 mg/kg in implanted HCT116 tumors, MGCD0103 was detectable in plasma 24 h after dosing, and for the first 8 h the concentration was at or above the IC50 values needed to inhibit the HDAC1 and HDAC2 enzymes in vitro. Induction of histone H3 acetylation in tumors peaked 2 – 8 h post-dose and was detectable up to 24 h [21]. In beagle dogs, MGCD0103 was determined to not be an inhibitor in the human ether-a-go-go related gene (hERG) flux assay, suggesting minimal QTc prolongation liability [22]. 3.3

Fatigue was dose-limiting with all schedules studied (Table 2). The mechanism of fatigue observed in patients treated with MGCD0103 was investigated by testing the thyroid function and measuring the cytokine IL-6 plasma levels [22]. Overall, no clear correlation of fatigue with either MGCD0103 dose, thyroid function or plasma IL-6 induction was observed. Hematological and biochemical effects did not appear to be consistently associated with MGCD0103 in clinical studies (Table 2). The most common hematological effects seen to date include anemia, neutropenia, lymphocytopenia and thrombocytopenia in the acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) trials only where such adverse events are not unexpected as part of the disease process in this patient population. Biochemical effects observed in the clinical setting included rare cases of grade 3 liver abnormalities, hyponatremia and hypophosphatemia. One patient experienced prolongation of the QTc interval, which appeared in the presence of hypokalemia and corrected with adjustment of electrolytes [23]. Two heavily pretreated patients with Hodgkin’s lymphoma died on study and association with MGCD0103 was deemed possible, one patient died of unknown cause and the other of neutropenic fever and sepsis [24].

Clinical development Safety and tolerability

3.3.1

Fatigue and constitutional symptoms, as well as gastrointestinal symptoms, were the most common adverse experiences (> 25% of patients overall) seen across completed studies to date.

Pharmacodynamics

In human cancer cells, MGCD0103 induced core histone H3 and H4 acetylation at low µmolar doses. Moreover, the ability of MGCD0103 to induce histone acetylation correlated well with its ability to inhibit a subset of class I HDAC enzymes. In past clinical trials with other HDACi, pharmacodynamic effects in patients were monitored by analyzing induction of histone acetylation in peripheral white blood cells using immunoblotting, enzyme-linked immunosorbent assay (ELISA) or fluorescence-activated cell sorter (FACS) [25,26], or in tumor tissues by immunohistochemistry [26,27]. These assays detected the level of acetylated histone H3 using an antiacetylated H3 histone antibody. Peripheral white blood cells needed to be permeabilized to allow the antibody to become fixed to acetylated H3 histones. However, the sensitivity of these assays and the limitation of clinical materials available for testing have rendered their use challenging. In addition, these assays which rely on purified enzymes or lysates may not necessarily reflect in situ activity, since their preparations are likely to disrupt normal protein–protein interactions. Therefore, an HDAC assay using a cell-permeable HDAC small-molecule substrate in intact peripheral white blood cells from patients was developed [28]. To date, pharmacodynamic studies that accompany the clinical evaluations of MGCD0103 have shown that this agent is capable of inhibiting HDAC enzyme activity, as measured by this assay, and that this inhibition correlates with induction of histone acetylation [22-24,29-32]. The results of these companion studies have shown dose-dependent increases in the inhibition of HDAC activity in clinical trials of both solid tumors and hematological malignancies. Although no evidence of clear correlation between


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Table 2. Summary of clinical studies with MGCD0103. Agent(s) [ref.]

Phase

No. of patients

MGCD0103 schedule

Reported DLT(s)

Recommended dose (RD)

Weekly dose intensity at RD

MGCD0103 single agent [33]*

I

27

daily × 2w q 3w

Fatigue

NA

NA

MGCD0103 single agent [22]

I

38

×3 weekly × 2w q 3w

Nausea, vomiting, fatigue, anorexia, diarrhea

45 mg/m2 (∼ 85 mg)

90 mg/m2 (∼ 170 mg)

MGCD0103 + gemcitabine [29]

I/II

47

×3 weekly (no rest)

Nausea, vomiting, fatigue, diarrhea, DVT, mental status changes

90 mg

270 mg

Solid tumors

Acute myeloid leukemia and myelodysplastic syndrome MGCD0103 single agent [30]

I

29


Nausea, vomiting, fatigue, diarrhea

60 mg/m2 (∼ 110 mg)

180 mg/m2 (∼ 340 mg)

MGCD0103 single agent [23]

I

24


QTc prolongation‡, fatigue, weakness

66 mg/m2 (∼ 120 mg)

132 mg/m2 (∼ 240 mg)

MGCD0103 + 5-azacitidine [31]

I/II

37


Nausea, vomiting, anorexia, diarrhea, dehydration

90 mg

270 mg

33


Neutropenic sepsis, fatigue, LFTs abnormalities, pneumonia

85 mg§

255 mg

38


Urinary frequency, LFTs abnormalities, pericardial effusion, edema, anorexia, low-voltage QRS

85 mg§

255 mg

Hodgkin’s lymphoma MGCD0103 [24]

II

Non-Hodgkin’s lymphoma MGCD0103 [32]

II

*Trial closed prematurely. ‡Occurred in presence of hypokalemia, and corrected with correction of electrolytes. §The initial dose of 110 mg for patients enrolled in these phase II studies has been reduced to 85 mg for poor tolerance reasons. DLT: Dose-limiting toxicity; DVT: Deep vein thrombosis; LFTs: Liver function tests; NA: Not applicable.

HDAC inhibition assessed by these assays and clinical outcome has been demonstrated so far, these findings have contributed as a proof of mechanism of action for MGCD0103. 3.3.3

Pharmacokinetics

Pharmacokinetic data in animal models revealed good oral bioavailability. In cancer patients, MGCD0103 demonstrated a favorable pharmacokinetic profile with a dose-dependent exposure [22-24,29-32]. Regardless of the schedule used, terminal half-life was independent of dose, and was 7 – 11 h. There was little accumulation with repeated dosing, suggesting that there is unlikely induction of metabolic clearance pathways, or of inhibition of drug elimination, by the parent drug or metabolites. Pharmacokinetic analyses demonstrated interpatient variability, which was improved by co-administration of MGCD0103 with low pH beverages, such as soda or carbonated soft drinks [22]. 3.3.4

Clinical efficacy in solid tumors

Two different schedules have been studied in patients with advanced solid tumors. The first was a daily schedule 1250

with 14 days of consecutive administration followed by a 7-day rest period, every 3 weeks [33]. MGCD0103 was not well tolerated at low doses, with patients experiencing dose-limiting fatigue. This trial was closed prematurely, as a less frequent administration schedule appeared to be better tolerated. Indeed, in a second Phase I study, in which MGCD0103 was given orally three times weekly for 14 days followed by 7 days’ rest every 3 weeks, the recommended daily dose was established at 45 mg/m2, corresponding to a fixed dose of 85 – 90 mg [22]. No objective tumor responses were observed among 32 patients assessable for response. Nevertheless, five patients with previously progressive colorectal, renal cell and lung cancers had stable disease > 4 cycles. MGCD0103 had been shown to interact synergistically with gemcitabine to inhibit pancreatic cell growth in vitro and pancreatic tumor growth in vivo [34]. As a result, a Phase I/II trial was initiated with MGCD0103 given three times weekly without rest in combination with gemcitabine administered at 1000 mg/m2 weekly for 3 weeks in 4-week cycles in patients with advanced solid tumors [29]. The dose-limiting toxicities observed included those expected with


Le Tourneau & Siu

both drugs given as single agents, including diarrhea, fatigue, nausea and vomiting, and deep-vein thrombosis. Grade 3 mental status changes were reported in one patient treated at 110 mg, without further details. The recommended dose for MGCD0103 in this combination has been established to be the same as that for MGCD0103 administered as a single agent (90 mg). Pharmacokinetic analysis showed similar MGCD0103 exposures when compared with historical data from monotherapy trials. Among 20 patients evaluable for clinical response in the Phase I part, two gemcitabine-naive patients with pancreatic cancer had a partial response and two other patients had an unconfirmed partial response. 3.3.5

Clinical efficacy in hematological malignancies

In AML/MDS, two schedules of MGCD0103 have also been studied in Phase I trials. In the first, MGCD0103 was given orally three times weekly with no rest week [30]. The recommended daily dose was 60 mg/m2, corresponding to a fixed dose of 110 mg. Three patients achieved complete response of the marrow blasts at the recommended dose, with a corresponding maximal HDAC inhibition at the time of best response. The second schedule studied was MGCD0103 given orally twice weekly without rest week [23]. The established recommended Phase II daily dose was similar (66 mg/m2). Nevertheless, the corresponding dose intensity with the latter schedule is lower than that offered by the first schedule. Preclinical studies had shown that MGCD0103 and 5-azacitidine, a hypomethylating agent, synergistically inhibited proliferation of human T-cell leukemia cells. As a result, a Phase I/II study in AML/MDS was initiated with 5-azacitidine administered subcutaneously at a standard dose (75 mg/m2) daily for 7 days, and with MGCD0103 started on day 5 of 5-azacitidine on a three-times-weekly schedule [31]. There were no rest periods between the 4-week treatment cycles. The recommended Phase II dose of MGCD0103 was determined as a 90-mg fixed dose. Among 52 enrolled patients, 19 patients (36%) had an objective response. Moreover, 10 of 23 patients (43%) treated at the recommended dose had an objective response. A randomized Phase III study using this combination regimen with the 90-mg dose for MGCD0103 versus 5-azacitidine alone in AML/MDS is planned. 3.3.6

Clinical efficacy in lymphoproliferative diseases

In preclinical studies, MGCD0103 exhibited significant biological activity in lymphoma models. A Phase II trial of MGCD0103 is ongoing in patients with relapsed and refractory classical Hodgkin’s lymphoma [24]. Most patients had previous bone-marrow or stem-cell transplants. Patients enrolled in this study received MGCD0103 at 110 mg fixed dose three times weekly in 4-week cycles. Following the enrollment of 23 patients, an alternative starting dose of 85 mg was evaluated in an effort to reduce the number of patients requiring dose modification for adverse events such as

gastrointestinal toxicities and fatigue. Among 23 patients enrolled at the 110 mg starting dose, 21 were evaluable, of whom 2 (10%) had complete response and 6 (29%) had partial response, thus achieving an objective response of 38%. The two patients with complete response are still progression-free after > 270 and > 420 days. One additional patient (5%) had stable disease for ≥ 6 cycles and 10 (48%) had stable disease for < 6 cycles. Preliminary data from the 85-mg cohort revealed that all five evaluable patients (among 10) experienced tumor reductions of ≥ 30%, including one patient having a partial response. Median duration of response was 5 months. Serum levels of a known prognostic factor in Hodgkin’s lymphoma, plasma thymus and activationrelated chemokine were decreased from baseline by at least 40% in five patients who achieved objective responses. A Phase II study of MGCD0103 was also performed with the same schedule in patients with relapsed or refractory non-Hodgkin’s lymphoma [32]. The trial contained two cohorts of patients with diagnoses of either diffuse large B-cell lymphoma (DLBCL) (n = 33) or follicular lymphoma (FL) (n = 17). Among 34 evaluable patients, one patient with DLBCL (3%) had a complete response, four patients (three patients with DLBCL and one with FL) (12%) had partial response, and 22 patients (65%) had stable disease. 4.

Conclusions

Overall, MGCD0103 appeared to be well tolerated at doses ≤ 90 mg fixed dose administered two to three times weekly, and appears to display antitumor activity in hematological malignancies as well as in lymphoproliferative diseases. As has been the case for many orally administered molecularly targeted agents, a more convenient fixed recommended dose has been established, replacing dosage based on body surface area. Most common side effects were manageable and include fatigue, nausea and vomiting. Consistently, hematological toxicities have been mostly observed in patients treated for hematological malignancies. Combinations of MGCD0103 with 5-azacitidine in AML/MDS, and with gemcitabine in solid tumors, have shown no overlapping toxicities, allowing the administration of all regimen drugs at their full dose concentrations. Rest weeks incorporated in some schedules did not seem to enable an increase of the daily dose of MGCD0103, but rather led to a decreased dose intensity. In addition, though the drug is given with resting intervals between doses, the fact that pharmacodynamic effects are sustained for up to 48 – 72 h post-dosing should improve tolerability without compromising antitumor activity. A novel HDAC enzyme assay has been developed and utilized in these studies of MGCD0103, and appears to be more sensitive than histone acetylation assays that had been used previously in other trials of HDACi. In addition, it provides rapid results, using few peripheral white blood cells from patients, and should be utilized in future studies of


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MGCD0103 and other HDACi. Nervertheless, a correlation between HDAC inhibition and clinical outcome remains to be demonstrated. 5.

Expert opinion

It is still not clear whether isotype-selective targeting of a particular HDAC, compared with broad HDAC inhibition, will result in improved HDACi efficacy [35]. Nonetheless, data are emerging that class I HDAC enzymes are of important clinical relevance [36]. It has been shown that targeted disruption of both HDAC1 alleles in mice results in embryonic lethality at very early stages of development, mainly due to arrested cell growth [37]. Similarly, studies using small interfering RNA (siRNA) to selectively knock down class I HDAC1 and HDAC3 in HeLa cells provide further evidence that class I HDACs are essential for cancer cell proliferation and survival [36]. In addition, it has been demonstrated that knockdown of class I HDAC8 by siRNA has antiproliferative effects in numerous cancer cell lines, suggesting that this isoform may also be an important target for cancer therapy [38,39]. Finally, HDAC2 has also been identified to be important with respect to cell proliferation and survival [40]. In contrast, siRNA-mediated inhibition of the class II HDAC4 and HDAC7 did not result in either morphological changes or antiproliferative effects in cancer cells [40]. Similarly, class II HDAC6 inhibition did not cause significant cell growth inhibition in solid cancer cells [41,42]. These findings suggest that targeting individual HDACs within class I may be more appropriate than targeting the entire class of enzymes. One can speculate that the greater specificity will correspond to modulation of a smaller number of disease-focused genes and a reduced toxicity profile. Thus, MGCD0103 may possibly have an increased therapeutic index over other broad-spectrum HDACi.

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The potential therapeutic advantage of isotype-selective HDACi over broad-spectrum HDACi is still largely theoretical at this stage. So far, toxicity profiles do not seem to differ between these two classes of HDACi, and it is too early to draw conclusions about potential differences in terms of therapeutic effects. For instance, although preclinical in vitro and in vivo studies have shown a superior efficacy of MGCD0103 over vorinostat (broadspectrum HDACi) and MS-275 (another class I isotypeselective HDACi), there are no direct clinical comparisons of these agents to support or refute such findings [21]. Nevertheless, class I isotype-selective HDACi such as MGCD0103 may display several advantages over other broad-spectrum HDACi: i) they have a longer half-life than hydroxamic acid derivatives, and allow therefore two- or three-times-weekly dosing schedules; ii) in contrast to cyclic peptides, they have an oral formulation; and iii) unlike cyclic peptides, they do not a priori display any cardiac toxicity [43,44]. Finally, MGCD0103 is the first isotypeselective HDACi to show promising antitumor activity in refractory Hodgkin’s lymphoma that has no approved therapy. Maturation of results from ongoing and planned studies of MGCD0103 will provide further evidence on the role of this HDACi in cancer therapeutics.

Acknowledgements The authors thank Dr Robert Martell and Dr Zuomei Li of MethylGene, Inc. for providing assistance with the manuscript.

Declaration of interest L Siu has received clinical trial funding from MethylGene, Inc. C Le Tourneau is supported in part by a grant from the Fondation de France.


Le Tourneau & Siu

mechanisms of action. Oncogene 2007;26:5541-52 Excellent review on the mechanisms of action of HDAC inhibitors.

22.

Siu LL, Pili R, Duran I, et al. Phase I study of MGCD0103 given as a 3-times-per-week oral dose in patients with advanced solid tumors. J Clin Oncol 2008;26:1940-7

Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 2007;5:981-9 Comprehensive up-to-date review of clinical trials with HDAC inhibitors.

23.

Lancet JE, Nichols G, Assouline S, et al. A phase I study of MGCD0103 given as a twice weekly oral dose in patients with advanced leukemias or myelodysplastic syndromes (MDS). Proc Am Soc Clin Oncol 2008 [abstract 2516]

12.

Peart MJ, Smyth GK, van Laar RK, et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA 2005;102:3697-702

24.

13.

Gui CY, Ngo L, Xu WS, et al. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA 2004;101:1241-6

Bociek RG, Kuruvilla J, Pro B, et al. Isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 demonstrates clinical activity and safety in patients with relapsed/refractory classical Hodgkin Lymphoma (HL). Proc Am Soc Clin Oncol 2008 [abstract 8507] First publication to show impressive antitumor activity of a HDAC inhibitor in Hodgkin’s lymphoma.

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Affiliation Christophe Le Tourneau & Lillian L Siu† †Author for correspondence University of Toronto, University Health Network, Princess Margaret Hospital, Division of Medical Oncology and Hematology, 610 University Avenue, Suite 5-718, Toronto M5G 2M9, Canada Tel: +1 416 946 2911; Fax: +1 416 946 4467; E-mail: [email protected]