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Role of Histone Deacetylase Inhibitors in the Treatment of Lymphomas and Multiple Myeloma
Hematology/Oncology Clinics of North America, 3, 26, pages 671 - 704
Keywords: Histone deacetylase inhibitors, Lymphoma, Multiple myeloma, Epigenetic therapy.
- Histone deacetylase inhibitors (HDACI) are epigenetic agents that affect the acetylation and deacetylation status of histones and other proteins, resulting in effects on gene expression and other important cellular functions.
- Epigenetic deregulation has been demonstrated in the pathogenesis of all types of lymphoma.
- HDACI as single agents have shown remarkable clinical activity in lymphomas, especially T cell lymphomas.
- The mechanism of the antilymphoma activity of HDACI is unknown.
- HDACI can be administered both orally and intravenously. They are well tolerated in the clinical setting, with a manageable side effect profile.
- Combining HDACI with other anticancer therapies, including cytotoxic therapies and targeted agents, is a promising new approach to the treatment of lymphomas.
Epigenetic processes are a means of affecting gene expression without altering the DNA nucleic acid sequence.1, 2, and 3 They are implicated in carcinogenesis, and epigenetic modification is an area of intense oncologic research for anticancer therapies in various human malignancies. 4 There are 3 fundamental modification processes that are of biologic significance in oncology: (1) acetylation and deacetylation of histones catalyzed by histone acetyl transferases (HATs) and histone deacetylases (HDACs); (2) genome methylation of CpG islands controlled by methylation and demethylation enzymes; and (3) small silencing RNA (siRNA)5, 6, and 7 that blocks gene expression. From a clinical perspective, biologic agents that modify the acetylation status of histones are important in the treatment of lymphoid malignancies. Presently, 2 HDACIs, vorinostat and romidepsin, are approved for the treatment of relapsed and refractory cutaneous T cell lymphomas (CTCL),8 and 9 and romidepsin is also approved for the treatment of relapsed and refractory peripheral T cell lymphomas (PTCL). 10
Histone acetyl modifications occur in the context of nucleosomes, that are recurring packaging structures of 146 base pairs of DNA wrapped around a core of 8 histone proteins. 11 The amino end of these histone proteins extends outwards and can be modified by chemical process like acetylation, methylation, and phosphorylation modulated by the respective set of opposing enzymes that control these chemical reactions. By affecting their secondary structure, these modifications change the spatial relationship of the histone proteins, with the DNA strand making it more or less poised for the transcription machinery to reach the DNA strand and start the process of gene transcription and protein expression. Specifically, acetylation of the ɛ-amino moiety on the lysine tails of histones leads to an open or transcriptionally active state of chromatin allowing transcription to proceed. In contrast, deacetylation of lysine results in a closed, condensed chromatin that prevents access of the transcription machinery to the DNA strand, thus silencing transcription. These reactions are catalyzed by 2 major classes of enzymes, referred to as HATs and HDACs. There is another class of enzymes, called histone deacetylase inhibitors (HDACIs), which can block the function of HDACs by binding to and inactivating the catalytically active pocket of HDACs. 12 This prevents or reverses the deacetylated state of the histone and promotes transcription just like HATs. However, HDACIs are distinct from HATs and to date several compounds have been identified as having HDACI-like properties. They have therapeutic potential as anticancer agents as discussed below. There are other posttranslational modifications that can affect lysine and other amino acid residues on histones, as well as other cellular proteins, and secondarily affect their function. These modifications include methylation, ubiquitinylation, phosphorylation, glycosylation, and sumoylation. The proteins affected include, but are not limited to, transcription factors like p53, E2F, c-Myc, nuclear factor kB(NF-kB), hypoxia inducible factor (HIF-1a), estrogen, and androgen receptor complexes; DNA repair enzymes like Ku70; heat shock proteins (HSP) like HSP-90; signaling pathway intermediaries like signal transducer and activation of transcription 3 (STAT 3); and structural proteins like α-tubulin. 13 There are several reviews on epigenetic and posttranslational modification. This article focuses on the emerging role of HDACIs in the treatment of lymphomas and multiple myeloma (MM).
Biology of HDACs
More than 18 different HDACs have been identified to date based on their homology to yeast proteins, 14 as shown in Table1 . Class I, II, and IV HDACs require Zn2+ as a cofactor in their active site and are generally inhibited by pan-HDACI, but data are now emerging regarding the newer HDACIs that have selective activity against specific isoenzymes (eg, tubacin is an HDACI that only blocks the action of HDAC6). Class III HDACs, also known as sirutins, are homologous to the yeast Sir 2 protein 15 and require nicotinamide adenine dinucleotide (NAD+) as a coenzyme and are not affected by pan-HDACI. To date, there are no data to suggest that inhibiting one HDAC rather than another has any clinical benefit. The clinical significance of selective HDACs inhibition remains unclear.
|Class||Yeast Homologous Protein||HDAC Enzymes||Cellular Location||Unique Domains||Required Cofactor|
|IIa||Hda1||4,5,7||Shuttles between nucleus and cytoplasm||—||Zn2+|
|IIb 148||6,10||Shuttles between nucleus and cytoplasm, contain 2 deacetylase domains, HDAC6 has α tubule deacetylase domain||—||Zn2+|
|III 14||Sir2||1,2,3,4,5,6,7||Deacetylase nonhistones and transcription factors (p53)||—||NAD+|
Abbreviations: Zn2+, Zinc; NAD+, Nicotine adenine dinucleotide.
Biology of HDACI
HDACIs are classified into 4 structural groups that vary in their potency and their ability to block various classes of HDACs, as shown in Table 2 . Besides the effects of HDAC inhibition on the acetylation status of histones, these enzymes can affect other cellular proteins, which can lead to a myriad of biologic effects downstream. Hence they should more appropriately be called protein deacetylase inhibitors. Some of the salient biologic effects of HDACI that have been observed in vitro include1, 13, 16, 17, and 18 (1) cell cycle arrest in the G1-M, G2-M phase; (2) induction of apoptosis mediated by effects on proapoptotic and antiapoptotic mechanisms for cell death affecting both the extrinsic and intrinsic apoptotic pathways; (3) inhibition of angiogenesis; (4) increased production of reactive oxygen species (ROS) and their effects on apoptosis; (5) acetylation of tubulin and disruption of aggresome formation; (6) changes in α tubulin affecting cell motility and differentiation; (7) effects on tumor immunity via effects on T cell receptor function, cytokine milieu of immune effector cells, as well as direct upregulation of proteins on malignant cells that enhance cellular recognition by antigen presenting cells (APCs) and other immune effectors. Table 3 highlights the mechanistic pathways and proteins that are affected by HDACIs leading to the effects listed earlier. In summary, modulation of histones and other proteins alter pathways that promote proliferation, angiogenesis, differentiation, and survival in cancer cells.
Potency in Vitro (IC50)
|Compounds||Isoenzyme Selectivity||Pharmacologic Profile|
|Short-chain fatty acids (mM)||Valproic acid 150||Class I, IIa (1, 2, 3, 8, 4, 5, 7)||Short plasma half-life, rapid metabolism, nonspecific mode of action|
|Phenylbutyrate 151||Class I, IIa (1, 2, 3, 8, 4, 5, 7)|
|Vorinostat (SAHA) 151||Class I, II
HDAC (1, 2, 3, 8, 4, 5, 6, 7, 9, 10)
|Belinostat (PXD 101) 151||Class I, II
HDAC (1, 2, 3, 8, 4, 5, 6, 7, 9, 10)
|LAQ824 151||Class I, II
HDAC (1, 2, 3, 8, 4, 5, 6, 7, 9, 10)
|Panobinostat (LBH589) 151||Class I, II
HDAC (1, 2, 3, 8, 4, 5, 6, 7, 9, 10)
|Tubacin 24||Class IIb
HDAC 6: no effect on histones, hyperacetylates α-tubulin
|MGCD0103 152||Class I
HDAC (1, 2, 3, 8)
|Romidepsin 153||HDAC 1, 2 > 4, 6||—|
|MS-275 152||Inhibits class >HDAC3
Does not affect HDAC 6, 8
|Niacinamide||Class II specific HDACI||—|
Abbreviations: IC50, inhibitory concentration of 50%; mM, millimolar; nM, nano molar; μM, micromolar.
|Extrinsic pathway 154 of apoptosis (activation of caspase 8, 3, 6, 7 via external receptors on cell surface. Engages the death-induced signaling complex)||Fas, Apo/TRAIL, death receptors DR4, DR5154, 155, and 156||cFLIP, cIAP2, and XIAP 156||Independent of p53 status, 157 can overcome the antiapoptotic effect of Bcl-2 158|
|Intrinsic pathway of apoptosis (activation of caspase 9, 3 from increased mitochondrial permeability and release of cytochrome C into the cytosol: tightly managed by Bcl-2 family of proteins and the BH3-only proteins)159 and 160||Bax, Bak||BcL-2, BcL-xL159 and 160||—|
|Cell cycle arrest: G1/M, G2/M 161||P27, p21, p1637 and 161||Cyclin A, cyclin D 161||Affects the balance between cell cycle regulators and their inhibitors like CDK4, CDK2 causing cell cycle arrest|
|Inhibits angiogenesis162 and 163||Inhibitors like thrombospondin, von Hippel-Lindau factor||VEGF, hypoxia-inducible factor, surviving in vascular endothelial cells||Decreased vascularity in tumors37 and 164|
|Transcription regulators||RB, CREB, p 53, BcL-6165, 166, 167, 168, and 169||—||Transcriptional repression of oncogenes|
|Proliferation||JAK/STAT pathways, b-TGF pathways, p53 (proliferation), Rel A/p65 (NF-kB), Myc family of proteins affecting proliferation, HIF-1 α141, 168, and 170||—||Decreased cell growth, inhibition of oncogenes|
|Signaling mediators||Estrogen receptors, androgens, glucocorticoids168 and 171||—||Decreased growth signals|
|DNA repair||KU70, FEN1, BRCA1, RAD51168 and 172||—||Increased cellular damage and activation of the apoptotic pathways|
|Chaperone proteins||Hsp-90, which affects ubiquitinylation and proteasome degradation in the acetylated state173 and 174||—||Effects on proteasomes and aggresomes|
|Disruption of kinetosome assembly||Effects on the phosphorylation status of premitotic proteins 175||—||Affects mitosis|
|ROS176 and 177||Apoptosis||—||—|
|Disruption of aggresomes||Acetylation of tubulin 66||—||—|
|Tumor immunity, autophagy 72||Effects on T cell receptor function, cytokine milieu of immune effector cells, as well as direct upregulation of proteins on malignant cells that enhance cellular recognition by APCs and other immune effectors178 and 179||—||Antitumor immune response|
Abbreviations: TRAIL, tumor necrosis factor–related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor.
Rationale for activity in lymphoid malignancies
HDACIs have shown efficacy against the treatment of lymphomas, and T cell lymphomas in particular. From a mechanistic perspective, it has been difficult to assign a mode of action of this class of drugs to any lymphoma, let alone CTCL or PTCL. Pharmacodynamic studies have demonstrated histone acetylation in peripheral blood mononuclear cells as well as 19 tumor tissue from patients with T cell lymphoma following treatment with HDACIs; however, there is no correlation of this with clinical response to these agents. Given the pleiotropic effects of HDACI on cellular function, it is important to delineate the mechanism of their antilymphoma effects and to link them to known pathways in lymphomagenesis. The known information is discussed below.
In general, cancer cells show a high level of expression of HDAC isoenzymes and hypoacetylation of histones. 20 This has been shown in comparisons of biopsy samples of lymphomas with normal lymphoid tissue, as well as colon cancer compared with normal colonic epithelium.21 and 22 Transformed cells are more sensitive to the effect of HDACI-induced apoptosis in comparison with normal cells. Aberrant expression of HDACs has been shown in lymphoid malignancies. 23 Both cell line data and primary tissue sample studies have supported the differential expression of HDACs across reactive nodes versus lymphoma subtypes mostly involving HDAC2s. 23 How this translates into lymphomagenesis or the sensitivity of these diseases to HDACIs is unclear. More useful data come from patient samples in various lymphoma subtypes. Class 1 HDACs (1, 2, 3, 8) were expressed in all non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) cases, whereas class II expression was variable with class 10 being present in all, but HDAC6 being present mainly in B cell lymphomas with plasmacytoid differentiation and HD. 23 The class II HDAC6 has one of the most variable expressions among lymphoid malignancies. It has several unique properties and is known to affect the acetylation status of several proteins including α-tubulin, which is important in the regulation of microtubule stability and function. 24 In addition, it may serve as a molecular chaperone, and plays a role in regulating the aggresome pathway that eliminates misfolded protein similar to the ubiquitin-proteasome pathway. Misfolded proteins are thought to be degraded either via the ubiquitin-proteasome pathway, or possibly through the aggresome. 25 Misfolded proteins destined for the aggresome are thought to be transported along microtubules, via the activity of motor proteins like dynein and adapters proteins like HDAC6, to the microtubule organizing center (MTOC), which in turn transports these proteins to the lysosome for degradation as part of the HDAC6-aggresome pathway. Pharmacologic inhibition of HDAC6 results in hyperacetylation of tubulin and disruption of the aggresome-mediated pathway resulting in apoptosis, which may also explain the mechanistic basis for their synergy with proteasome inhibitors (PI) as discussed below. Overexpression of HDACs may result in the decreased expression of tumor suppressor genes, leading to carcinogenesis. One oncogenic mechanism that may involve aberrant HDAC expression includes the recruitment of HDACs to promoter regions of key genetic sequences.26, 27, and 28 It has been shown that specific chromosomal translocations in leukemias lead to expression of oncogenic fusion proteins that form aberrant association with HDACs at promoter site genes and leading to the onset of tumorigenesis. This process is exemplified by the translocation t (15,17) in acute promyelocytic leukemia (APL) that results in the fusion promyelocytic leukemia–retinoic acid receptor (PML-RAR) (APL), that recruits the HDAC3-containing repressor complexes leading to a decreased expression for differentiation-specific genes.29 and 30 Similarly chromosomal translocations resulting in the recruitment of class I HDACs to oncogenic promoter sites may underlie the pathogenesis of T cell NHL. Overexpression of repressive transcription factors that interact with HDACs and affect the promoter regions of tumor suppressor genes may also underlie the pathogenesis of hematological malignancies.
Tumor microenvironment and tumor immunology play important parts in the pathogenesis and progression of most lymphomas and HD. HDACs and HDACIs are shown to be important regulators of the immune response and induction of tolerance. Villagra and colleagues31 and 32 have demonstrated that overexpression of HDAC11 inhibits interleukin (IL) 10 expression and induces inflammatory antigen presenting cells that are able to prime naïve T cells and restore the responsiveness of tolerant CD4+ cells. Disruption of HDAC11 in APCs leads to the upregulation of expression of the gene encoding for IL-10, leading to impairment of T cell responses, which may contribute to their antilymphoma effects.
There is likely to be further delineation of the effects of various HDACIs on specific cellular functions. There is currently no evidence that inhibiting one HDAC enzyme rather than another is associated with improved activity, or that more selective HDACIs will be associated with an improved adverse effects profile.
Further discussion of HDACIs in specific lymphoma subtypes is presented below.
HDAC Modulation of T Cell Lymphomas
CTCL is the disease with the highest clinical response rates with HDACIs. A large study of the expression of various HDACs in 73 patient samples has correlated this with the clinical behavior. 33 The expression of HDAC1 and HDAC6 was similar between indolent and aggressive cases but the expression of HDAC2 and acetylated histone 4 (H4) was higher in cases of aggressive disease (HDAC2 55.5% aggressive CTCL vs 15% indolent, acetylated H4 22% aggressive vs 8%). Survival correlated with the overall expression of HDAC6 (hazard ratio 0.39) independently of the CTCL subtype. Other epigenetic markers were also deregulated in CTCL. Van Doorn and colleagues34 and 35 compared genome wide DNA methylation screening in samples of CTCL with benign skin disorders. They showed widespread promoter hypermethylation in malignant T cells in CTCL, suggesting epigenetic instability. Specific CpG islands of more than 35 promoter regions were hypermethylated including the tumor suppressor gene BCL7a (B cell chronic lymphocytic leukemia [CLL]/lymphoma) in 48% of samples, PTPRG (protein tyrosine phosphatase receptor γ) gene in 27% of samples and THBS4 gene thrombospondin 4) in 52% of patient samples. These genes were also hypermethylated in the CTCL cell lines but not in the control samples. BCL7, located on chromosome 12q 24.3, is of particular importance because it has been cloned as part of the chromosomal translocations seen in Burkitt lymphoma. Its expression is diminished in mycosis fungoides and PTCL compared with lymphoblastic lymphoma. Other genes that were hypermethylated in CTCL samples compared with normal skin are grouped into the following categories: cell cycle deregulation (p15, p16, p73), defective DNA repair genes (MGMT), apoptosis deregulation (TMSI, p73), and chromosomal instability (CHFR). Hypermethylation of p73 has also been described in nodal B cell lymphomas and natural killer (NK) cell lymphomas. Promoter hypermethylation of P16 has also been noted in CD30+ T cell NHL.
For further mechanistic insight into the action of HDACIs in CTCL, Duvic and colleagues 36 attempted to look at biologic correlatives of HDACI therapy in patients with CTCL by performing serial skin biopsies on patients receiving vorinostat on trial at 2 hours, 4 hours, 8 hours, and then 12 weeks after initiation of treatment. These results established the following: at 4 weeks, 39% of the patient samples showed lymphocyte depletion consistent with the antilymphoma effect of vorinostat. At 4 weeks after therapy, there was a decrease in dermal microvessel density as measured by CD31 positivity on dermal vessels in all patients, but this was significantly lower in responding patients (P = .001). Prior cell line data using the CTCL cell line HH indicated that a 24-hour exposure to vorinostat resulted in an 8-fold increase of the antiangiogenic protein TSP-1 as studied by gene expression array. Consistent with the cell line data, an increase in the dermal TSP-1 staining was noted as early as 2 hours after treatment and was present at 8 weeks in 6 of the 17 paired lesions, including 4 of the 6 responders. Another important protein that is constitutively activated in CTCL is phsophorylated STAT-3 (p-STAT3), which can be detected by immunohistochemical stains either in the nucleus or cytoplasm within both the keratinocytes and the lymphocytes in the lesions. In this study, nuclear staining for p-STAT3 was prominent in both keratinocytes and lymphocytes before the start of therapy. After 4 weeks of therapy with vorinostat, the staining pattern shifted to localization within the cytoplasm (inactive state) in 9 of the 11 patients who responded, whereas this shift was noted in only 3 of the 16 nonresponders. This shift was noted as early as 2 hours after treatment in 4 of 11 paired lesions. Using a similar model of paired skin biopsies, Ellis and colleagues 37 performed gene expression profiles (GEP) and real-time quantitative polymerase chain reaction (PCR) on skin samples from 6 patients with CTCL who were being treated with panobinostat in a phase I trial. These biopsies were obtained at 0, 4, 8, and 24 hours after administration of drug. In this study, there were 10 patients with a diagnosis of relapsed CTCL who were treated at varying dose levels as part of a large phase I study in patients with hematological malignancies. Clinical efficacy was observed in 8 patients (2 achieved a complete remission-CR at both dose levels and 4 patients achieved a pa partial remission-PR, 2 patients had stable disease-SD). The skin biopsy data showed that there was hyperacetylation of histone H3 in tumor cells as early as 4 hours after treatment. Consistent with previous data, histone acetylation within mononuclear cells was shown in both responders and nonresponders up to 48 to 72 hours after the last oral dose, indicating that this could not be used as a therapeutic marker. GEP data from all 6 patients consistently showed that panobinostat induced transcriptional regression of a greater number of genes than activation. The genes that were consistently affected included genes affecting cell cycle (CCNDI, IGFI) apoptosis (septin10, TEF, SORBBS2), angiogenesis (GUCY1A1, ANGPT1), and immune modulation (LAIR1). CDKN1A, which codes for p21, was unregulated in response to HDACI therapy, although in this study upregulation of p21 was not consistently seen in all patients. Of the 23 genes, 4 were further selected for validation by QRT-PCR. These data confirmed downregulation of guanylate cyclase 1A3 (GUCY1A3), the proangiogenic gene ANGPT1a, and the transcription factor COUP-TFII (NR2F20, which is an upstream regulator of ANGPT1 and CCND1). These effects on genes controlling angiogenesis are consistent with the effects noted by Duvic and colleagues 36 and provide confirmation that the antiangiogenic effects of HDACI therapy may be important in their mechanism of action. Bates and colleagues 38 conducted a clinical trial of romidepsin in patients with PTCL and CTCL and also studied the biologic correlates of activity of HDACI in peripheral blood and tumor samples. Predetermined markers of HDACI activity included global histone acetylation and expression of the ABCB1 gene (encodes for the p-glycoprotein called mixed drug resistance) and fetal hemoglobin. The histone acetylation data correlated with pharmakokinetics parameters of area under the curve (AUC) and maximum plasma concentration Cmax, though there was no correlation between response, histone acetylation, and the expression of either ABCB1 or fetal hemoglobin, indicating the need for improved biomarkers to predict responses with HDACI.
HDACIs an affect signaling patterns from cell surface receptors and, increasingly, T cell malignancies are associated with deregulation of the T cell receptor (TCR) signaling and the immune function. Investigations into the effects of HDACIs, particularly vorinostat have been conducted on TCR signaling and the immune system to delineate more specific mechanisms of action for this agent, as well as to understand the basis for combining it with other agents. Wozniak and colleagues 39 performed extensive studies using GEP on a panel of CTCL cell lines (HH, HUT78, MJ, Myla, SeAx) that were exposed to vorinostat at various time points. The functional analysis of these altered genes revealed pathways including cycle regulators for G1/S transition (E2F, E2F4, cyclin-dependent kinase [CDK] 4, CDK6, cyclin A2, D2, D3, E20), G2/M regulators (CDC23, CD25B, and CHEK4), apoptosis (FAS, IRAK1, CASP6, BID, BCL2), antiproliferative genes, as well as multiple mitogen-activated signaling kinase (MAPK) signaling pathway (MAPK1, MAP3K6, MAP3K14) as described earlier. However, this study also showed changes in genes that are involved in the JAK/STAT signaling pathway, cytokine-cytokine interaction, and expression of receptors belonging to the tumor necrosis factor (TNF) family, all important pathways for survival and differentiation of lymphocytes and the immune system. Vorinostat treatment was shown to shift the expression profile of cytokines, resulting in increased expression of IL-1a, IL-6, and Il-9, and a decrease in the expression of IL-4, IL-5, Il-10, IL-11, and their associated receptors. Overall, the cytokine profile represented a state that inhibited lymphocyte growth and proliferation and inhibited the TH2-type immune responses. The latter aspect of the drug effect is important because CTCL is a malignancy of activated T cells and is characterized by deregulation of the immune system with reversal of the Th1/Th2 cytokine profile. Vorinostat has also been shown to affect genes that affect cell migration and chemotaxis, which may affect the skin homing properties of malignant cells in CTCL including a decrease in the expression of cytokine genes like CCL1, CCL22, CXCL10, CCR4, and CCR6 and an increase in others like CCR2 and CCR6. There was also some alteration in the expression of members of the JAK/STAT pathway like STAT6, STAT5A, and SOCS2 (decrease), and STAT1, STAT3, and JAK1 (increase).
The TCR 40 signaling pathway is crucial for the survival of T cells and is altered in T cell malignancies. HDACI have been shown to modify this pathway. In general, antigen stimulation engages TCR signaling and induces the recruitment of several kinases including lymphocyte-specific protein tyrosine kinase and a protooncogne named FYN, resulting in phosphorylation of many downstream substrates including CD3 chains, TCR ɛ chain, and the ζ chain associated with ZAP-70 and phospholipase C. Several downstream pathways that are activated include the PKC, MAPK/p38, Jun pathway and the serine-threonine protein kinase PI3K/AKT pathway, which is important for the survival of T lymphocytes. Treatment with vorinostat induces repression of all genes associated with TCR-related signaling including ZAP-70, CD3DIL4, IL-5, Il-10, and FOXP3, and upregulates FYN, interferon γ, and IL-12A. The effects on TCR signaling were significant and were seen across all cell lines and confirmed by QT-PCR. A decrease in the phosphorylated forms of ZAP-70 and AKT after vorinostat treatment was confirmed by Western blots, confirming the inhibitory effects of this agent on TCR signaling. FYN, which is upregulated by vorinostat, is an tyrosine kinase that belongs to the SRC family kinases that phosphorylates several negative regulators of TCR signaling and ultimately adds to the negative effect of vorinostat on TCR signaling pathways.
In summary, there are many signaling pathways that may be altered in T cell NHL, and HDACI seem to affect them in a myriad of different ways. As this knowledge of this increases, it will be logical to combine multiple targeted agents to optimize the antilymphoma effects of these agents.
HDAC Modulation of B Cell Lymphomas
Presently, there are no HDACIs that are approved specifically for the treatment of B cell lymphomas, although there is a strong rationale for their use in B cell malignancies. Mantle cell lymphoma (MCL) is considered to be incurable with known therapies and is a unique disease characterized by marked deregulation of cyclin D1 mediated by the t(11:14) translocation and loss of the CDK inhibitors p21 and p27. 41 Two of the most prominent effects of HDACI are the downregulation of cyclin D1 and upregulation of p21/p27. 42 The clinical data of HDACI in MCL are promising and represent an interesting avenue for combination therapy to treat this disease. Similarly, the association of deregulated BCL-6 in many cases of diffuse large B cell lymphoma (DLBCL) and the effects of HDACI on BCL-6 provide a rationale for the use of HDACI either alone or in combination with other agents in cases of lymphoma in which BCL-6 is over expressed. 43 DLBCL is one of the most common subtypes of NHL and has 2 subtypes based on gene expression analysis. 44 The more common subtype is the germinal center (GC) subtype that overexpresses BCL-6 and CD10, whereas the activated B cell (ABC) subtype expresses activation markers like MUM1 and/or CD138. The ABC subtype has low levels of BCL-6 but high levels of NF-kB and STAT3 and is more chemorefractory, leading to a worse prognosis for the patients. The overexpression of the transcription factor Bcl-6 in DLBCL (GC) from chromosomal translocations leads to recruitment of several HDACs including HDAC1, 2, 4, 5, and 7, which causes the repression of growth-regulatory target genes like p53, p21, 45 and STAT3. 46 Bcl6 can be inhibited by acetylation (through HDACI therapy as well as through inhibition of SIR-2) and leads to the activation and expression of p53, resulting in downstream effects like apoptosis. 45 In ABC subtypes, HDACI can result in decreased expression of STAT3 through its association with HDAC1, resulting in inhibition of activated STAT3 and its dephosphorylation, leading to growth inhibition of this subtype as well. STAT3 is also a transcriptional target of Bcl-6 but, in contrast with p53, it functions as an oncogene.23 and 47 These data provide a rationale for the use of HDACI in DLBCL (both GC and ABC subtypes) and has formed the basis of an ongoing trial using a combination of HDACI and Sir-2 inhibitors for the treatment of GC B cell lymphomas.
HDAC Modulation of Hodgkin's Disease
In vitro data support the potential activity of HDACIs against HD cell lines. Biologically, HD is characterized by a high level of cytokine secretion from the inflammatory infiltrate surrounding the pathognomonic Reed-Sternberg (RS) cells.48 and 49 Therapeutic strategies include targeting the malignant cells as well as the inflammatory milieu and cytokines including, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, and thymus activation–regulated chemokine (TARC/CCL17), which are important in the pathogenesis of HD. Many of these are part of an autocrine loop thought to activate the JAK/STAT pathways, resulting in continual activation of the STAT family of transcription proteins, in particular STAT3 and STAT6. Cytokines including IL-2, IL-6, IL-7, IL-9, IL-10, and IL-15 induce the activation of STAT3, whereas STAT6 is primarily induced by IL4 and IL-13 and may depend on an autocrine IL-13 loop secreted by RS cells. 50 Phosphorylated STAT6 localizes to the nucleus and induces the expression of STAT6 target genes that include TARC and IL-13 as well as other cytokines that attract TH2-specific lymphocytes into the tumor microenvironment. 51 These lymphocytes are involved in humoral immunity and promote allergic responses, which suggests the importance of STAT6 in the survival of RS cells as well as promoting the unique cellular and immunologic milieu that is a hallmark of HD. STAT regulation involves phosphorylation as well as lysine acetylation, which implies that HDACIs could play a role in regulating critical features of HD biology. 52 This is supported by data from Buglio and colleagues, 53 where they demonstrated that exposure of HD cells (L-428 and KM-H2) to vorinostat resulted in an increase in histone acetylation and p21 expression, and caspase-mediated apoptosis. Vorinostat selectively inhibited STAT6 phosphorylation and resulted in decreased mRNA levels of STAT6 seen by PCR and a reduction of TARC as a downstream effect. Changes in cytokines were evaluated in the supernatants of exposed cells showing an increase in the level of IL-13 and interferon inducible protein (IP)-10, and a significant decrease in the level of IL-5, confirming a shift in the Th1/Th2 cytokine balance. Another target gene regulated by STAT6 is the antiapoptotic Bcl-xL, which was significantly decreased in the HD cell lines following vorinostat exposure. This reduced level of Bcl-xL could reduce the apoptotic threshold enough to allow synergistic activity with other anti-HD agents including chemotherapy. Combinations of HDACI with hypomethylating agent can also influence antitumor immune responses by affecting the expression of proteins like the cancer testis antigens (CTA), which include MAGE, SSX, and NY-ESO, in a variety of tumors including Hodgkin lymphoma (HL). 54 These immunomodulatory effects may underlie the therapeutic activity of these agents in HL.
HDAC Modulation of MM
In contrast with lymphomas, there are no studies showing abnormal expression of HDACs in plasma cell malignancies like myeloma. In spite of this, several HDACIs have shown antimyeloma activity. The mechanism of this activity remains unclear but may be related to the general effects of HDACIs on cell biology, like upregulation of p21, cell cycle arrest, or apoptosis. Preclinical data support antimyeloma activity with HDACI, as shown by the modulation of gene expression in MM cells by HDACIs.55 and 56 Both suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) alter the expression of oncogenes, cell cycle regulators, antiapoptotic transcription factors, and members of the IGF-IR and IL-6R signaling cascades, important in the pathogenesis and progression of MM. In addition, VPA has been shown to alter genes that contribute to RNA splicing and transcription as well as DNA replication, indicating effects on cell growth that are independent of cell cycle regulation and apoptotic pathways.57 and 58 These data are consistent with the effects of HDACIs shown in other cell lines.
Direct cytotoxic effects of HDACIs have been reported in various myeloma cell lines, indicating differences in potency between the different agents: sodium butyrate and valproate acid being the least potent (inhibitory concentration of 50% [IC50] in mM),57, 59, and 60 FK228 and LBH589 are the most potent in myeloma.61 and 62 The antimyeloma apoptotic effect is independent of IL-6, a key growth factor for MM cells.60, 62, and 63 Coculturing the MM cells with bone marrow stromal cells did not protect the cells from death, indicating that HDACIs could overcome the protective effect of the stromal microenvironment, which is one of the key clinical issues in MM.63, 64, 65, and 66 Mechanistically, the antimyeloma effects of HDACIs seems to involve both the extrinsic and intrinsic apoptotic pathways.67 and 68 MM cells contain high levels of Bcl-2 and Mcl-1 and lower levels of Bax compared with normal plasma cells, making them more resistant to apoptosis.67 and 69 VPA resulted in the redistribution of death receptor (DR4) to lipid rafts, resulting in improved DR4-related signaling and restoring the sensitivity of U266 MM cell lines to APO21/TNF-related apoptosis-inducing ligand (TRAIL)–induced apoptosis. 70 LBH586 resulted in the activation of caspase 8 and the downregulation of the gene TOSA, which is a negative regulator of Fas ligand (FasL). 61 Treatment with LBH589 caused apoptosis of the cell line MMIS (malignant melanoma in situ) by affecting the translocation of mitochondrial proteins like cytochrome c and apoptosis-inducing factor; upregulation of Apaf-1; and cleaving of Bid, caspase 9, and caspase 3. 62 SAHA also decreased the expression of the antiapoptotic protein FLICE-like inhibitory protein (FLIP) and other members of the inhibitors of apoptosis (IAP) family such as X-linked IAP (XIAP). 71 This process resulted in the sensitization of the MM cells (MMIS) to a Fas-activating monoclonal antibody (CH-11) and to recombinant TRAIL. Treatment of the MM cell lines U266, as well as primary myeloma cell lines, with HDACIs resulted in decreased expression of the antiapoptotic proteins Mcl-1, Bcl2, and Bcl-xL, and an increase in Bax. 62 Both LBH589 and SAHA resulted in poly-ADP-ribose (PARP) cleavage in MM cells by 2 distinct mechanisms involving caspase 3 and calpain. Overexpression of the antiapoptotic protein Bcl-2 inhibited SAHA-induced apoptosis in MM cells.61 and 71 Another HDACI named KD5170 resulted in Bax activation and cleavage of caspases 9 and 3, resulting in activation of the intrinsic apoptotic system in U266 cell lines. 65 Autophagy is another method of cell death and HDACIs have been shown to affect this pathway as well.72 and 73 Schwartz and colleagues 58 showed that VPA-treated myeloma cells had cleavage of caspase 3 and autophagy granules, the first observation of this nature.
All HDACIs except tubacin induce cell cycle arrest in G1/S phase by affecting cyclins, especially cyclin D, and their CDKs. The balance is maintained by the balance between these kinases and their inhibitors like p16, p21, and p27. In MM, constitutive phosphorylation of the Rb protein may be fundamental to the growth and development of the tumor, as indicated by the increased levels of cyclins in G1compared with healthy plasma cells. In MM, HDACI-associated cell cycle arrest is associated with induction of p21 as well as a reduction of cyclin D1 and D2, thus affecting the transition of cells from G1 to S and resulting in arrest at this stage. 55
Another important antimyeloma action of HDACI involves degradation of misfolded proteins in the cell 74 via the ubiquitination-proteasome and the aggresomal protein. The aggresomal system is particularly important in MM. Aggresomes are formed by the retrograde transport of misfolded proteins on microtubules and travel to the MTOC where they are sequestered for lysosomal degradation. Movement along the microtubules involves intact microtubules and the motor dynein. HDACs deacetylate α-tubulin and play a key role in the aggresomal pathway by affecting the motility of proteins along the microtubule.75 and 76 Targeting HDAC6 with tubacin or a pan-HDACI such as vorinostat or LBH586 results in hyperacetylation of the α-tubulin, accumulation of polyubiquitinated proteins, and apoptosis. 66 Tubucin can inhibit the growth of MM cell lines, both drug-sensitive (eg, MMIS, U266, INA-6, and RPMI8226) and drug-resistant cell lines (eg, RPMI-LR5 and RPMI-Dox40) with an IC50 between 5 and 20 μM, but no cytotoxicity is seen in normal peripheral mononuclear cells. Thus tubacin selectively targets malignant cells independently of the drug resistance state of these cells. 77 The linkage between inhibition of an HDAC and the proteasome pathway has raised a strong mechanistic rational for the combination of these agents in the clinical setting, much of which is centered on the unfolded or misfolded protein response.
Vorinostat has been shown to suppress the expression of receptor genes involved in MM cell proliferation, survival, and migration, like IGF-1R, IL-6R and its key signal transducer gp130, TNF-R, CD138 (syndecan-1), and CXCR-4. 55 Vorinostat also suppressed the autocrine IGF-1 production and paracrine IL-6 secretion of bone marrow stem cells by triggering MM (MMIS) cell binding, suggesting that it can overcome cell adhesion–mediated resistance. NaB reduced IL-6R in cell lines. Increased p21 expression and apoptosis were observed in these cell lines along with lines that were transfected with an expression vector of IL6-R, indicating that downregulation of IL-6R is not required for HDACI-induced apoptosis, again emphasizing the many pathways affected by HDACIs in MM cells. 55
HDACIs also affects angiogenesis in MM by a direct effect on growth and differentiation of endothelial cells and the downregulation of proangiogenic genes in tumor cells. Using OPM-2 and KM3 cell lines, VPA has been shown to decrease vascular endothelial growth factor (VEGF) secretion and VEGF receptor expression, resulting in inhibition of the vascular tubule formation in endothelial cells in cocultures with myeloma cells.60, 78, and 79
De Bruyne and colleagues 80 showed that CD9, a tetraspanin, shows an inverse correlation between its expression level and tumor metastasis in solid tumors. In MM, CD9 is downregulated and treatment with LBH589 could result in its upregulation, making it more susceptible to NK cell–mediated cytolysis. Its expression is correlated with nonactive MM disease. This finding indicates that the immunologically mediated effects of HDACI are also importation in MM.
Pharmacology of HDACI
HDACIs are a chemically diverse group of naturally occurring and synthetic molecules ( Fig. 1 ) that inhibit the activity of HDACs in a wide range of concentrations from low nanomolar to high millimolar,1 and 81 as listed in Table 3 . Presently, there are at least 18 different HDACI being evaluated in preclinical and early clinical trials that target the Zn2+-dependent (ie, class 1, 2, and 4) HDACs. Most HDACI have a short plasma half-life (vorinostat, 2 hours 82 ; romidepsin, 3 hours 83 ; MGCD0103, 9 hours 84 ) and undergo hepatic metabolism either via the CYP450 system (romidepsin) 83 or the glucuronidation system (vorinostat). 82 The metabolites are excreted through the biliary and fecal routes. HDACIs have varying formulations and differing side effect profiles depending on the route of administration. The 2 agents approved by the US Food and Drug Administration (FDA) to date (namely vorinostat and romidepsin) have undergone extensive pharmacokinetic monitoring as part of the clinical trials that led to their approval. One of the earliest pharmacologic studies was performed with vorinostat,19 and 82 first with the intravenous (IV) preparation and then with the oral formulation. A direct comparison of the toxicity and pharmacokinetic profiles of IV versus oral vorinostat revealed that the Cmax of exposure to vorinostat was higher with the IV formulation versus oral formulation (2408 ng/mL vs 658 ng/mL) but the AUC was greater with the oral route of exposure (4634 h × ng/mL vs 101,854 h × ng/mL). The toxicity profiles of these 2 regimens were also different, with more thrombocytopenia, dehydration, and diarrhea noted with the oral formulation compared with the IV. Oral vorinostat (the approved formulation) is 71% bound to proteins and is metabolized via glucuronidation and hydrolysis followed by β-oxidation into 2 inactive metabolites. Biotransformation by cytochrome P450 is negligible. It is excreted by the kidneys with less than 1% of the dose recovered as unchanged drug in the urine. The mean urinary excretion of the 2 pharmacologically inactive metabolites at steady state was 52% (±13.3%) of the vorinostat dose; 16% (±5.8%) of the dose as O-glucuronide and 36% (±8.6%) of the dose as 4-anilino-4-oxobutanoic acid. Romidepsin is highly protein bound in plasma (92%–94%) over the concentration range of 50 ng/mL to 1000 ng/mL with α1-acid-glycoprotein (AAG) being the principal binding protein. In contrast with vorinostat, it undergoes extensive metabolism in vitro, primarily by CYP3A4 with minor contributions from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro. 83
In clinical trials, the histone acetylation (H3 and H4) in mononuclear cells in the peripheral blood is considered to be a biomarker for reaching a target during administration of HDACI. 82 In the case of vorinostat, the effect can persist for up to 10 hours after the drug has cleared from the system after an oral dose. As shown by Kelly and colleagues, 82 higher doses of vorinostat did not necessarily produce more acetylated histone, but generally resulted in a longer half-life of the acetylated H3/H4. Despite the role of H3/H4 acetylation, accumulation of acetylated H3/H4 can be shown in every patient, and accumulation of the Ac-H3/H4 does not correlate with response. Identifying appropriate surrogate biomarkers of response with HDACIs continues to be a major research goal.
Side Effect Profile
The side effect profile of all HDACIs is uniform across even the diverse chemical classes of agents.42, 85, 86, and 87 The most common side effects include fatigue, nausea, and diarrhea. Transient thrombocytopenia is the most common myelosuppressive effect. During the phase 1 experience with vorinostat, bone marrow examination of patients at their platelet nadir revealed a normocellular marrow with dysplastic-appearing megakaryocytes that seemed to have impaired platelet budding. 19 Subsequent studies revealed that HDAC inhibition may repress the GATA-1 gene, an important transcription factor for hematopoiesis, leading to a delay in megakaryocyte maturation and thrombocytopenia. 88
One of the recurring themes of therapy with HDACIs is the cardiac effects of these agents. Prolongation of the corrected QT (QTc) interval has been observed as a class effect for many HDACIs and is thought to occur via the HERGK+ channels.89 and 90 A systematic study of cardiac events resulting from treatment with romidepsin (282 administered cycles of romidepsin and more than 700 doses of the drug) showed that almost all patients had prolongation of the QTc interval (median 14 milliseconds) and more than half the patients had transient electrocardiogram (EKG) changes, including T wave flattening and ST depression.91 and 92 These changes were clinically insignificant, with no change in cardiac enzymes or cardiac function. The agent is now approved, with the caution that the treating physician should be careful in giving the drug to patients who may have a significant cardiac history or be susceptible to prolongation of the QTc interval. It is recommended that attention be paid to maintaining the patient's potassium and magnesium levels within the normal range while receiving therapy with romidepsin. Because of the early experience with romidepsin, most trials with HDACIs now require rigorous cardiac monitoring. It is also recommended that patients with baseline prolonged QTc, significant heart disease, or patients on medications that may prolong the QTc interval be excluded from trials with HDACIs. Various HDACIs also vary in their cardiac effects. For example, vorinostat is not associated with any serious cardiac toxicity, whereas the hydroxamic acid panobinostat (LBH589) and its predecessor LAQ824 are associated with QTc interval prolongation (1 patient had torsades de pointes) There were no reported long-term changes in the EKG in any of the patients treated on trials of HDACI.
Thrombosis and pulmonary embolism are other important adverse events noted on the pivotal vorinostat trials (2 patients experienced thrombosis and pulmonary embolism). It was unclear whether this was directly related to the drug, but it is recommended that caution be used while using vorinostat in patients who may have an underlying thromboembolic disorder. An increased incidence of thromboembolic events has not been reported on the ongoing clinical trials with HDACIs.
HDACI in lymphoma (clinical data)
B Cell Lymphoma
B cell NHL are the most common lymphomas and include subtypes that vary from some of the most aggressive tumors (Burkitt lymphoma) to some of the most indolent (follicular lymphoma [FL] and small lymphocytic lymphoma). In spite of combination cytotoxic agents, immunotherapies, and radioimmunotherapies, relapsed and refractory disease states remain a major clinical problem, particularly in indolent lymphomas. One of the earliest demonstrations of activity of an HDACI in B cell lymphoma was reported with VPA, a weak HDACI, which induced a complete remission in a patient with multiply relapsed transformed FL. 93 VPA has been more widely studied in myeloid leukemias, with little to no other experience in lymphoid malignancies. It is a potent inhibitor of STAT3 (overexpressed in the ABC type of DLBCL). 94
In addition to VPA, there have been several early phase trials with a variety of other HDACI for the treatment of B cell NHL. Kelly and colleagues 82 reported on the first phase 1 study of intravenously administered vorinostat (previously known as SAHA) in patients with hematological malignancies. Of the 11 patients with B cell malignancies (HL n = 5, NHL n = 6), no patients with B cell NHL responded, although antitumor activity was seen in 2 patients with HD, including a 30% reduction of tumor burden in 1 patient that was maintained for 3 months, and stable disease in another patient for 8 months. A follow-up phase 1 study conducted by the same investigators 19 with an oral formulation of vorinostat revealed a favorable side effect profile and a maximum tolerated dose of 400 mg per day given for 14 consecutive days on an every-21-day cycle. This study enrolled a total of 25 patients with hematological malignancies, with the best response being a complete remission (CR) seen in a patient with transformed FL. Partial remissions (PRs) were seen in patients with transformed lymphoma and mycosis fungoides. A patient with HD had a 31% decrease in disease lasting for 10 months. These 2 studies of vorinostat in patients with solid tumors and hematological malignancies were among the first to show the potential activity of these compounds in B cell malignancies and HL. Another phase 1 trial of oral vorinostat was conducted in patients with B cell malignancies, as reported by investigators in Japan. 95 This trial enrolled 10 patients with B cell lymphomas at 2 dosing levels: 100 mg and 200 mg twice a day for 14/21 days. Four of the 10 patients responded, including 2 CRs and 1 PR seen in patients with FL and 1 PR in a patient with MCL. A dedicated phase 2 study of vorinostat in patients with relapsed DLBCL at a dose of 300 mg twice a day (14 days per 3 weeks or 3 days per week) has been reported. 96 Eighteen patients were enrolled, with 1 patient obtaining a CR lasting 468 days, and 1 patient who attained stable disease for 301 days. Based on this study and the collective experience from the phase 1 studies, it was concluded that vorinostat did not exhibit impressive single-agent activity in large B cell lymphoma. However, the maximal tolerated dose (MTD) that is now given on the label for vorinostat was not used to assess response in these studies and, based on the phase 1 experience by Duvic and colleagues, 36 this dose was poorly tolerated. A second phase II study evaluated vorinostat at a dose of 200 mg twice a day for 14/21 days in patients with relapsed and refractory indolent NHL.97, 98, and 99 This trial enrolled 33 patients (FL, 20; MCL, 8; marginal zone lymphoma [MZL], 7), of whom 6 patients achieved a CR, 4 attained a PR, and 4 had stable disease for an overall response rate (ORR) of 29% (CR+PR). Responses were limited to FL (40%) and MCL (28%), with no responses seen in MZL. Although the single-agent activity of vorinostat in DLBCL is variable, and probably low, these experiences raise 2 questions: (1) why do select patients achieve CR, whereas others do not; and (2) is the optimal pharmacokinetic profile and dosing of this agent different for these diseases?
One strategy to improve the efficacy of HDACIs in B cell lymphomas has been to evaluate more potent HDACI in the treatment of B cell lymphomas to look for stronger signals of activity. Most phase I trials are conducted to include the broad category of lymphoid diagnoses that initially encompass both B and T cells with the idea of expanding the trial to a specific subtype if a positive signal is found in a specific diagnostic group. Belinostat, a potent hydroxamic acid HDACI, is currently in development for the treatment of lymphoma, in particular peripheral T cell lymphoma (PTCL). Similarly to vorinostat, it has an oral and IV formulation, although most data collected to date are with the IV formulation. 99 The initial phase I trial of belinostat in advanced solid tumors established an MTD of 1000 mg/m2 given intravenously for 5 days as a 30-minute infusion. This dose was confirmed as the MTD in a parallel study of the same agent in hematological malignancies, with no additional toxicity seen in this group of patients. 98 This study enrolled 11 patients (DLBCL n = 7, transformed CLL n = 2, transformed FL n = 4, CLL n = 2). No objective responses were seen in any patients, although some patients experienced stabilization of disease (DLBCL n = 2, CLL n = 3). For ease of administration, the oral formulation of belinostat is being developed and a phase 1 study of oral belinostat in patients with all subtypes of NHL is underway. The starting dose was 750 mg/m2, with planned escalations until the MTD is reached. Interim results are to reported at ASH (American Society of Hematology) 2011. 100 The MTD has been established at 1500 mg a day for 14 days in a 21-day cycle. Results have shown 1 CR (duration 2+ cycles) in patients with NHL, 1 PR (duration 8 cycles) in patients with HD, and stable disease has been noted in 12 patients (duration 1–24 cycles, median 1.5). Aside from the 1 CR and 1 PR, tumor shrinkage between 25% and 50% was noted in 8 patients. PCI-2478 is an orally administered HDACI belonging to the class of hydroxamic acid. Evans and colleagues 101 reported the results of the initial phase I data at ASH 2010. One patient with FL achieved a CR, whereas 4 PRs and 7 stable disease responses were noted in 20 other evaluable patients. This study showed that there are no cardiac effects or prolongation of the QTc interval noted with this agent. A phase II portion of the trial is planned.
Although the experience with HDACIs as single agents in B cell lymphoma has been disappointing, these drugs have important potential activity, and the future will probably involve rational combinations. It is important to gain a better understanding of how the various classes of HDACIs work in B cell lymphoma, and to try to develop reasonable hypotheses around how these agents are likely working in these DLBCL. With this experience, potentially important HDACI are likely to emerge in the near future.
T Cell Lymphoma
Mature T cell NHL and NK cell neoplasms comprise 12% of all NHL and 15% to 20% of aggressive lymphomas worldwide. They are characterized by great morphologic diversity and genetic variation even within individual disease entities. The current 2008 World Health Organization classification recognizes more than 20 types of mature T cell and NK T cell lymphomas (PTCL). 102 CTCLs are malignancies that arise in the skin and are classified as a separate entity based on their distinct clinical behavior and prognosis. 103 Among the aggressive lymphomas, a T cell phenotype confers a worse clinical outcome compared with their B cell counterparts, with the exception of ALK-positive anaplatic large cell lymphoma. Long-term survival at 5 years remains at 10% to –30% for most histologies with present treatment strategies, 104 and relapsed/refractory disease remains a significant clinical dilemma.
For reasons that are not clear, HDACIs have shown consistent and promising activity in the treatment of many types of T cell lymphoma. Two agents of this class, vorinostat (Zolinza) and romidepsin (Istodax), have been approved for the treatment of relapsed or refractory CTCL in the United States.8 and 9 In addition, romidepsin is also approved for the treatment of relapsed and refractory T cell lymphoma,105 and 106 whereas belinostat and panobinostat are in clinical trials for T cell malignancies. 107
Vorinostat was the first HDACI approved for the treatment of cancer. In the United States, this agent is approved for the treatment of CTCL in patients who have failed at least 2 prior systemic therapies. 8 Based on early signals of activity and a favorable toxicity profile in patients with lymphoma in the phase 1 experience, Duvic and colleagues 36 conducted a restricted phase I/II study of oral vorinostat in patients with CTCL. This phase 2 experience enrolled 33 patients with advanced, heavily pretreated CTCL. Three different orally administered dosages and schedules were sequentially evaluated: 400 mg daily; 300 mg twice daily for 3 days followed by 4 days of rest; and 300 mg twice daily for 14 days with a week of rest followed by 200 mg twice daily. The ORR was 24.4%, with 8 patients having a partial remission (PR), including 4 patients with Sézary syndrome (SS). More importantly, 14 of the 33 patients (42%) reported significant pruritus relief. The median time to response was 11.9 weeks, and the median duration of response was 15.1 weeks. The major side effects included fatigue, thrombocytopenia, and gastrointestinal symptoms (predominantly diarrhea and nausea). Within the different cohorts, more thrombocytopenia was noted in the third cohort in which patients received a higher dose (300 mg twice a day for 14 days straight). However, most of the responses were seen in groups 1 and 3. Thus, based on the response rate and toxicity criteria, the dose of 400 mg per day was established as having the best safety profile. This study affirmed the findings in the original phase 1 experience, supporting the daily dosing of 400 mg of vorinostat by mouth, which was associated with the most favorable side effect profile and highest response rate of any of the explored schedules. Based on these data, a registration-directed phase II study using the dose of 400 mg by mouth was initiated by Olsen and colleagues. 8 This study included 74 patients with CTCL who had failed at least 2 prior systemic therapies. Disease assessment was by modified skin-weighted assessment tools (m-SWAT). 108 This study showed an ORR of 29.7%, with 1 patient achieving CR after 281 days of therapy. Median time to objective response was 56 days (28–171 days); some patients took up to 6 months to respond and the median duration of response was not reached in the study, although it was greater than 185 days. Nonprogressing patients continued on the study with 15 patients receiving the drug for more than a year and 6 patients receiving it for more than 2 years. In addition, another 29 patients had clinical benefit manifested by stable disease for more than 24 weeks. Pruritus relief was found in 35 patients, including responders and nonresponders, again pointing to the effect of vorinostat on cytokine profiles. These data supported the approval of vorinostat by the FDA in October 2006, making it the first HDACI to be approved for the treatment of cancer.
Romidepsin (formerly known as depsipeptide, FK228) is a cyclic peptide originally isolated from the broth culture of Chromobacterium violaceum. 109 It was initially studied at the National Cancer Institute (NCI) in patients with refractory or relapsed solid tumors by Piekarz and colleagues 110 reported a patient with refractory PTCL that responded to depsipeptide. Because the drug began to show a consistent signal in patients with T cell lymphoma, the study was expanded to separate patients with CTCL from those with PTCL, and then it further stratified patients based on the amount of prior therapy they received. 105 Overall, it had a stratification that consisted of 7 different treatment arms, with the intention of separating different cohorts of patients with T cell lymphomas based on histology and prior number of therapies. All patients received drug as an intravenous infusion at a dose of 14 mg/m2 once a week in a three out of a four-week cycle. The 2 major cohorts were CTCL and PTCL and the data from these 2 groups of patients was analyzed and presented separately. Piekarz and colleagues 110 reported the results of 71 patients with relapsed CTCL that was treated with depsipeptide. The ORR was 34% (24/71) with complete remissions observed in 4 patients. The median duration of response was 13.7 months. Based on the data generated by the NCI, the drug was eventually acquired by Gloucester Pharmaceuticals, and 2 registration-directed clinical trials were launched, 1 in CTCL and 1 in PTCL. In the preparation of the new drug application to the FDA, data from the 2 studies (NCI plus Gloucester) were pooled and patients were analyzed using a composite end point to assess response using skin assessment, lymph node and visceral involvement, and abnormal circulating Sézary cells.9, 111, and 112 One-hundred and thirty-five patients were evaluable, with a median age of 57 years, and who had received a median of at least 2 (1–8) prior systemic therapies. One-hundred and three patients (76%) had at least a stage IIB or higher disease and 19 patients had SS. The ORR was 41%, with a complete remisson (CR) rate of 7% and duration of response of 14.9 months. On subanalysis, the response rate was 58% in patients with Sézary syndrome, which is impressive in a disease that is notoriously chemoresistant. 113 In addition, this study objectively evaluated pruritus using the visual scale analog (VSA), a tool that has been validated in other clinical trials, 112 and reported a relief of pruritus in more than 60% of the patients, including nonresponders. This agent was approved by the FDA for the treatment of relapsed CTCL following failure of 1 line of systemic therapy. For PTCL, the NCI trial included patients with PTCL who had failed at least 1 prior systemic therapy, further stratified into less than 2 or more than 2 prior systemic therapies. 10 There were 48 evaluable patients, and all pathology was reviewed centrally. The patients had received a median of 3 prior therapies, including 18 patients (38%) who had received a prior stem cell transplant. ORR was reported as 31% with 4 (8%) CRs. Patients who received more than 2 cycles of therapy had a response rate of 44%. Median duration of response was 9 months, with a median time to progression of 12 months. Coiffier and colleagues 106 reported the results of a second large multicenter phase II study of romidepsin in PTCL conducted by Gloucester Pharmaceuticals. The study enrolled 131 patients with histologically confirmed PTCL who had failed or were refractory to more than 1 systemic therapy and had measurable disease. The dosing schedule was the same as the NCI study (ie, weekly dosing of romidepsin at 14 mg/m2 on days 1, 8, and 15 every 28 days). The median age of patients was 59.4 years and they had received a median of 2 prior systemic therapies. In this study, 21 patients (16%) had received a prior stem cell transplant, ORR was reported as 34%, with 19 (15%) CRs and 15 (12%) PRs. Median duration of response was not reached because 16 patients with CR had not progressed at the time of analysis. These 2 studies established impressive single-agent activity of romidepsin in PTCL, and presentation of the collective data to the FDA has led to the approval of this agent in the setting of relapsed PTCL in which patients have failed at least 1 line of systemic therapy.
Belinostat is a hydroxamic acid with pan-HDACI activity that is currently in clinical trials for solid tumors and hematological malignancies, and is available in both oral and intravenous formulations. A phase I trial of the intravenous formulation was performed in parallel with the solid tumor phase and an MTD of 1000 mg/m2 was established.98 and 114 This formulation is being studied in a large phase II trial at a dose of 1000 mg/m2 for patients with relapsed PTCL. The oral formulation has also been developed and, as with vorinostat, it has been better tolerated than the IV formulation. In the ongoing phase I trial of oral belinostat in hematological malignancies, an MTD of 1500 mg given daily on days 1 to 14 in a 21-day cycle has been established and its activity is being explored in a variety of lymphomas.
Oral panobinostat, also known as LBH589, is a pan-HDACI belonging to the hydroxamic acid group that has shown activity in patients with CTCL in early-phase trials. 37 Six of 10 patients with CTCL showed a response in the original phase 1 trial at a dose of 20 mg and 30 mg given on Monday, Wednesday, and Friday (MWF) on a weekly basis. The trial has now been expanded to a dedicated phase II trial in patients with CTCL at a dose of 20 mg a day MWF given weekly. The interim results of this trial were reported at ASH 2010. 115 Ninety-five patients were enrolled with advanced (stage 1B–1VA) mycosis fungoides or Sézary syndrome. Of 62 patients, 11 responded by SWAT criteria, including 2 CRS. The trial is ongoing and further results are awaited.
HD is one of the most curable of lymphomas, but 20% to 30% of patients relapse after attaining remission, or have primary refractory disease. 116 Approximately 50% of these patients can be cured with second-line chemotherapy and autologous stem cell transplantation (ASCT). Treatment options are limited for patients who relapse beyond second-line therapy or have primary refractory disease. The median survival for patients after relapse following ASCT is 26 months, and there are an estimated 1300 deaths annually from HD in the United States.117 and 118 Novel therapies for these patients are needed.
There are several studies that consistently show that HDACIs have activity in HL. One of the earliest insights into this signal was revealed in the phase 1 experience with vorinostat. In the IV and oral phase 1 experiences with vorinostat,19 and 82 12 patients with relapsed or refractory HD were treated with escalating doses of vorinostat, with 4 patients responding as follows: on the IV study, 1 patient attained a PR that lasted for approximately 9 months; 1 patient experienced a 14% decrease in her lung disease, resulting in significant improvement of her performance status; and a third patient achieved a 42% reduction of the tumor, lasting for 2 months. On the oral study, 1 patient achieved a 31% decrease in tumor lasting nearly 10 months. A subsequent phase II trial of vorinostat 119 administered at 200 mg orally twice a day for 14 of 21 days produced only modest clinical activity, with only 1 patient achieving a PR. The phase 1 experience with oral vorinostat established an MTD of 400 mg given orally once daily for 14 days in a 21-day cycle.
Of the available HDACIs, panobinostat is being studied in a registration-directed phase 2 trial in HL. The initial phase IA/II trial of panobinostat (LBH589) used 2 different dose levels and schedules of this agent in patients with hematological malignancies. Patients with HD were entered onto the study at 2 dose levels: arm 1 was dosed at a starting dose of 30 mg a day given MWF every week, whereas arm 2 was initiated at 45 mg a day given on the same MWF every other week schedule. There were 13 patients with HD who were enrolled on the study, of whom 5 met the criteria for a partial response indicating evidence of HD activity. It appeared to be well tolerated, with fatigue, nausea, thrombocytopenia, and diarrhea being the most common side effects. The MTD was estimated by the logistic regression model and was defined as 40 mg a day given every MWF on the weekly schedule. Based on these data, a large international phase II trial of panobinostat is designed for patients with relapsed and refractory HD. The final results of the phase II portion were reported at ASH 2010. 120 Overall, 129 patients were enrolled, with a median age of 32 years. Patients were heavily pretreated with a median of 4 (2–7) prior regimens including autologous stem cell transplant (100%), allogeneic transplant (10%), and radiation (69%). Responses were observed in 35 of 129 evaluable patients (5 CRs, 30 PRs, and an ORR of 27%). At the time of presentation, 19 patients were still receiving treatment. Responses were durable, with a median duration of 6.9 months (4.1–51.3 months). The most notable adverse event was reversible thrombocytopenia. Another HDACI with activity in HL is MGCD0103, which belongs to the benzamide class. MGCD 0103 is classified as an isotype-selective HDACI that predominantly inhibits class 1 HDAC enzymes and is administered as an oral formulation. A phase II trial of MGCD0103 was conducted at a dose level of 110 mg given orally 3 times per week in patients with relapsed and refractory HD. 121 Responses were seen in 7 of the 20 patients who were treated at this dose level, including complete remissions; however, the dose was considered too toxic, requiring frequent interruptions and dose reductions. The protocol was then revised to lower the dose to 85 mg per day given on the same schedule. Another 10 patients were enrolled on the lower dose and partial responses were seen in 3 of the 10 patients. The agent was well tolerated, with the main side effects being fatigue and thrombocytopenia, although 2 patients developed pericardial effusions requiring an interruption of the protocol. Collectively, these data suggest that there is a signal of efficacy of some of the more potent HDACI in HD, but the biologic correlates of this activity are still unclear.
HDACI in MM
MM represents about 1% of all cancers and is the most commonly diagnosed hematological malignancy. The median age at diagnosis is 67 years, with an increasing incidence noted with older age groups. The clinical outcome of MM has improved greatly in the last decades. Novel agents like bortezomib, IMIDs, and stem cell transplantation have improved the median survival of patients with MM from an average of 2 to 3 years to more than 8 to 10 years. However, in spite of a plethora of treatment options, including stem cell transplantation, most patients with myeloma are destined to relapse and remain incurable because of the development of drug resistance governed by the bone marrow microenvironment. Therefore, newer targeted therapies are needed and HDACIs represent a new class of antimyeloma therapy, as discussed later.
Single-agent activity of HDACIs in MM has been disappointing. Richardson and colleagues 122 reported the first phase 1 study of SAHA in MM at various doses and schedules in 13 patients. One patient had a minor response and 1 had stable disease. In a study of PXD101 in patients with advance myeloma, only 1 patient with MM was found to have stable disease. Niesvizky and colleagues 123 reported on a phase 2 trial of the potent HDACI romidepsin for the treatment of refractory MM. Thirteen patients were enrolled and were treated at 14 mg/m2 given as a 4-hour IV infusion on days 1, 8, and 15 of a 28-day cycle. No patients had an objective response but 4/12 patients with secretory myeloma had evidence of M-protein stabilization and several patients experienced improvement of their bone pain and hypercalcemia, indicating some biologic effects of clinical benefit. Correlative studies were designed in this study of cell cycle kinetics as well as evaluation of several proteins including BCL-2, MCL-1, CD31, and cleaved caspase 3, and the results revealed no detectable modulation in vivo in these patient samples. The focus has now shifted to rationally based combinations of HDACI in MM, which are discussed later.
Combination Therapy in MM
Both preclinical and clinical data support the use of HDACI in combination with other agents. The most striking combination is with proteasome inhibitors (PI). Bortezomib an important antimyeloma drug that targets the proteasome system and NF-kB may target HDACs as well and may function as HDACI, further strengthening the rationale to use it in combination with HDACI. 124 Kikuchi and colleagues 125 reported that bortezomib can downregulate the expression of class 1 HDACs (HDAC1, HDAC2, and HDAC3) in MM cell lines and primary MM cells at the transcriptional level accompanied by histone hyperacetylation. Short interfering RNA-mediated knockdown of HDAC1 enhanced bortezomib-induced apoptosis, and its overexpression inhibited it. HDAC1 overexpression conferred resistance to bortezomib in MM cells and administration of the HDACI romidepsin restored sensitivity to bortezomib in HDAC overexpressing cells. Thus bortezomib targets HDACs via distinct mechanisms from conventional HDACIs.
Pei and colleagues 126 first showed that, in vitro, the combination of HDACI with bortezomib resulted in enhanced cellular toxicity compared with their effects as single agents. This synergy was associated with a reduction of NF-kB DNA binding activity, modulation of Jun N-terminal kinase (JNK) activation, and a ROS-dependent downregulation of cyclin D1, Mcl-1, and XIAP. Combining bortezomib with PXD101 caused oxidative stress accompanied by enhanced expression of Bim, DNA damage, MAPK p38 activation, and p53 phosphorylation. 127 Inhibition of aggresomal pathway by tubacin, together with proteasomal inhibition by bortezomib, also resulted in an accumulation of the ubiquitinated proteins followed by synergistic anti-MM activity. 77 The cytotoxicity was mediated by stress-induced JNK activation, caspase, and PARP cleavage. Bortezomib led to aggresome formation and further combining it with LBH586 or SAHA (both inhibit HDAC6) resulted in disruption of the aggresome and apoptosis.66 and 128 Bortezomib and SAHA resulted in an induction of the proapoptotic proteins BH3, Noxa, and endoplasmic reticulum (ER) stress, indicated by the disruption of calcium homeostasis and caspase 4 activation. Knockdown studies have shown that caspase 4 and Noxa play an important role in Myc-driven sensitivity of MM to the combination of bortezomib and SAHA. In MM, Myc expression is correlated with the intracellular ER content and protein synthesis rate. Anti-MM activity of the combination of PI with HDACI was shown in primary MM samples and cell lines.
The combination of vorinostat and boretezomib was first reported in 2 multicenter phase 1 studies and the results were presented at ASH 2008.129, 130, and 131 In the first trial, 34 patients with relapsed and refractory myeloma were enrolled. Patients received escalating doses of vorinostat (200 mg twice a day, 300–400 mg daily for 4 days) and bortezomib (0.7, 0.9, 1.1, or 1.3 mg/m2 on days 1, 4, 8, and 11). Cycles were repeated every 21 days. The highest doses of vorinostat (400 mg daily for 14 days and bortezomib 1.3 mg/m2) were given together and an MTD could not be reached. Nausea, diarrhea, thrombocytopenia, and vomiting were the most common adverse events. Results revealed that the best response was a PR in 9 (26%) patients, minimal response in 7 (21%) patients, and stable disease in 18 (53%) patients. The responders included previous bortezomib failures. The second trial enrolled 23 patients who received vorinostat (100–500 mg on days 4–11) and bortezomib (1–1.3 mg/m2 on days 1, 4, 8, and 11). Dexamethasone was added later in the cycles for varying degrees of responses (< PR, PD). The main toxicities were hematological. Of the 21 evaluable patients, 2 achieved a good PR, 7 PR, 10 stable disease, and 2 had progressive disease. Again noted were the responses amongst bortezomib-refractory patients and the acceptable 129 toxicity profile.
A study reporting the results of the combination of romidepsin, bortezomib, and dexamethasone for the treatment of MM was reported in Blood in August 2011. This phase 1 study was designed to determine the MTD of the triple drug combinations with a secondary objective of OR, TTP, and overall survival (OS). The final MTD-defined doses were as follows: bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; dexamethasone, 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12; and romidepsin 10 mg/m2 on days 1, 8, and 15 every 28 days. Main toxicities were thrombocytopenia and peripheral neuropathy. There were 2 (8%) CR and 13 (52%) PRs, including 7 very good PRs (VGPR). Median time to progression was 7.2 months and the median OS was 36 months.
Panobinostat is being studied in combination with velcade and dexamethasone. The phase 1 study of the combination with bortezomib enrolled 47 patients who received drugs at 5 different dose combinations. ORR was more than 70% and responses were seen at the lowest dose levels. The recommended dose at the end of the trial was panobinostat 20 mg orally to be given 3 times a week and velcade at 1.3 mg/m2 to be given twice a week for 2 weeks. Hematological toxicities, nausea, diarrhea, fever, fatigue, and weakness were the most commonly reported side effects. This work has led to an international phase 3 study of panobinostat in combination with velcade.
Panobinostat in combination with revilimid and dexamethasone is also a promising combination and the preliminary results of a phase 1B study were presented at ASCO 2011. Patients received panobinostat at 5, 10, 20, or 25 mg plus 25 mg of revilimid and 40 mg of dexamethasone. Forty-six patients were enrolled. Reported dose limiting toxicities (DLTs) were thrombocytopenia and a low white cell count. The final results are awaited.
Other promising combinations include hypomethylating agents and chemotherapeutic agents. Several key tumor suppressor genes are hypermethylated and hence deactivated in human malignancies. In MM, hypomethylating agents like 5-azcitidine and decitabine in combination with HDACIs can reactivate these genes, resulting in decreased tumor cell growth.132 and 133 Treatment of MM cell line U266 with NaB and decitabine resulted in an increased expression of the p16 gene and protein compared with either agent alone. 134 Similarly, the upregulation of the proapoptotic protein Bim could be enhanced significantly by LBH586 in combination with decitabine, whereas decitabine alone had no effect on this. 135 Clinical trials are underway to study this combination in MM. Many HDACIs, including LAQ824, romidepsin, and LBH586, have shown powerful synergy on growth inhibition and cytotoxicity when combined with alkylators like malphalan and dexamethasone.62 and 136 Enhanced apoptosis of MM cell lines has been observed with HDACIs and activators of TRAIL and Fas pathways.137 and 138
Novel Combinations of HDACI in Lymphoma
By targeting specific molecular pathways, HDACIs lend themselves to endless combinations with other targeted therapies. Combinations of HDACIs and the PI bortezomib have shown marked synergistic clinical activity in MM and MCL. Paoluzzi and colleagues 139 showed synergistic cytotoxicity of either belinostat or romidepsin in combination with bortezomib against a panel of MCL cell lines. This combination induced mitochondrial membrane depolarization and apoptosis in treated cells. A decrease in cyclin D and Bcl-xL was also shown. Combinations of vorinostat and bortezomib were also synergistic in MCL cell lines resulting in apoptosis, ROS generation, and decreased NK-kB activity. 140 The combination of vorinostat and bortezomib has also been evaluated in vitro for synergy against CTCL cell lines. This combination has shown an upregulation of p21 and p27, and an increased expression of phosphorylated p38, which participates in a signaling cascade controlling cellular responses to cytokines and stress. Decreased expression of VEGF was also shown after treatment with vorinostat and bortezomib. Similar synergy between romidepsin and belinostat with bortezomib has also been reported in CLL cell lines and has been shown to involve mechanisms of NF-kB inactivation and perturbation of the apoptotic pathways. 141 The novel PI carfilzomib is also being evaluated in combination with HDACI and has shown promising synergistic activity with vorinostat 142 in a DLBCL cell line. This activity was associated with activation of JNK and p38 MAPK, and decrease in NK-kB, AKT inactivation, and Ku70 acetylation. Clinical trials are now underway to evaluate the combination of proteasome inhibitors and HDACI for the treatment of lymphomas.
Bcl6 43 overexpression is a hallmark of DLBCL, particularly the GC subtype. In the deacetylated state, Bcl6 functions as a transcriptional corepressor of several genes that influence cell cycling and the tumor suppressor p53 activity. Sirtuin2-α, a class III HDAC, has been shown to interact and attenuate p53-mediated function. 143 The use of HDACI to acetylate and enhance the function of BCL-6 could provide a therapeutic target for antilymphoma therapy. This function can be further enhanced by combining this with nicotinamide, which can enhance p53 function to target BCL-6–addicted tumors. Clinical trials are underway to study this combination. 144
By lowering the apoptotic threshold, HDACI lend themselves as ideal agents to be combined with chemotherapeutic agents, a strategy that is being explored in solid tumors and other malignancies and will likely be explored in lymphoproliferative disorders. A phase I clinical trial in patients with advanced CTCL consists of vorinostat and escalating doses of bexarotene given daily for 28 days. At the time of writing, 19 patients have been enrolled and accrual is ongoing because MTD has not been reached. Responses have been reported in some patients. 145
DNA methylation is involved in malignancy and is seen, in progression, in more than 80% of all solid tumors. Methylation is one of the main physiologic processes to induce silencing of gene expression. The clinical use of demethylating agents like 5-azacitidine and decitabine has been developed in myeloid malignancies without any significant activity noted in lymphoid diseases. However, in vitro data support the combination of HDACI with hypomethylating agents to provide antilymphoma therapy, as shown by the combination of decitabine and romidepsin. 146
HDACIs have had significant effects on deregulated genes in lymphoma and MM. The clinical results of single-agent activity are promising against specific subtypes of lymphoproliferative agents.
The use of HDACIs has allowed pharmacologic manipulation of deregulated genes in cancer cells and HDACI have shown single-agent activity against T cell lymphomas, CTCL, MCLs, and HD. The bigger promise lies in the impact that these agents can have in enhancing the activity of other targeted therapies ranging from antifolates like pralatrexate to demethylating agents, proteasome inhibitors, and even cytotoxic agents. In addition, the effects of HDACIs on the immune system and cytokines, as seen in CTCL and HD, also indicate that HDACIs can be useful in the treatment of immune dysfunction underlying tumorigenesis, autoimmune disorders, and graft-versus-host disease. There is also an effort to determine whether class specificity of HDACIs has a biologic significance, and, as more information is obtained about epigenetic dysregulation in lymphoid diseases, the clinical significance of this will become clear. It is likely that in the future an HDACI-based therapy will be the backbone of both up-front and salvage therapies for most lymphomas and will lead to better outcomes compared with current cytotoxic therapies.
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