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Molecular biology of mantle cell lymphoma: From profiling studies to new therapeutic strategies
Blood Reviews, 5, 23, pages 205 - 216
Mantle cell lymphoma (MCL) is a well-defined lymphoid malignancy characterized by a rapid clinical evolution and poor response to current therapeutic protocols. The hallmark genetic alteration of MCL is the t(11;14)(q13;32) chromosomal translocation that leads to the overexpression of cyclin D1. Recently, new molecular alterations of major importance in the pathogenic mechanisms of this disease have been discovered, and have revealed the biological heterogeneity of MCL. The first section of our review discusses our current understanding of the molecular biology of this entity according to recent information from comparative genomic hybridization (CGH) and expression profiling studies, which are leading to the identification of several druggable targets. In the second section we revise new therapeutic strategies based on new drug families that target key molecular pathways of major relevance in this malignancy. We analyze emerging agents that are already producing significant results in different models of human cancers, including MCL. Based on the current knowledge and recent studies, we suggest that the encouraging results described here should provide a rationale platform for the design of new treatments that may overcome the resistance of this aggressive lymphoma to conventional therapy and improve patient prognosis.
Keywords: Mantle cell lymphoma, Genomic profiling, Therapeutic targets.
Mantle cell lymphoma (MCL) represents about 6% of non-Hodgkin Lymphomas (NHL), with an annual incidence of approximately 0.2–0.7/100.000 inhabitants/year. 1 Despite its low frequency, it is one of the most challenging lymphomas to treat, with a median overall survival of 3–4 years. 2 At least four morphological variants are recognized: classic, small cell, blastic and pleomorphic with some interplay between them.3 and 4 A differentiated immunophenotype is typically recognized, which is crucial for diagnosis. The classic immunophenotype includes a mature B cell population expressing CD5, CD19, CD43, weakly positive for FMC7, and negative for CD10, CD23 and bcl-6. 5
Clinically there is a male predominance and most patients present advanced Ann Arbor stages. Patients typically present lymphadenopathy, splenomegally and in most cases extranodal involvement, including bone marrow and liver. Interestingly, gastrointestinal involvement is also frequent, and in some series it has been reported to occur in more than 90% of cases. 6 Major changes have recently been implemented in the management of this disease, and consequently the current standard therapy achieves a high rate of complete remissions (CRs). However, the pattern of continuous relapses in the face of higher frontline responses still marks this disease as a challenge for clinicians.
Although the hallmark genetic lesion in MCL is the t(11;14)(q13;32) chromosomal translocation leading to cyclin D1 overexpression, new alterations involved in the molecular pathogenesis of the disease have been recently discovered, revealing the biological heterogeneity of MCL. Altogether, this knowledge might allow the design of new molecularly-targeted agents. We review herein the molecular biology of this entity, supported by recent data leading to the identification of new druggable targets with encouraging preclinical results and relevant preliminary clinical experience.
Molecular biology of mantle cell lymphoma
Cyclin D1 overexpression
The hallmark genetic alteration responsible for MCL pathogenesis is the t(11;14)(q13;32) chromosomal translocation that juxtaposes the CCND1 region on 11q13 with the immunoglobulin (Ig) heavy-chain joining region in chromosome 14q32. This translocation determines the ectopic and deregulated expression of cyclin D1 (CCND1). 7 Cyclin D1, which is not expressed in normal B lymphocytes, regulates the cell cycle transition from the G1 to the S phase by promoting the phosphorylation of the retinoblastoma protein (pRb) in combination with cyclin-dependent kinase 4 and 6 (CDK4 and CDK6). Current WHO guidelines for the diagnosis of MCL rely on morphological examination and immunophenotyping, with demonstration of cyclin D1 protein overexpression and/or the t(11;14)(q13;q32) translocation for confirmation. 8 However, some authors have described a subset of MCL cases that lack the t(11;14)(q13;q32) translocation and may represent a variant form of the disease.9, 10, and 11 These findings have been controversial, and have been attributed to suboptimal immunostaining, inadequate genetic or molecular analyzes or misdiagnosis. Recent microarray studies have shown that these cases are clinically similar to cyclin D1-positive MCL cases and that overexpression of either cyclin D2 or cyclin D3 may substitute for cyclin D1 deregulation,9 and 10 thus indicating the importance of the deregulation of the G1 machinery in the pathogenesis of these tumours. Moreover, the participation of additional regulatory mechanisms in the regulation of cyclin D1/CDK4 activity has become clear after the failed attempts to establish cyclin D1 as a dominant B-cell oncogene.12 and 13
Animal models of mantle cell lymphoma
Most studies aimed at generating MCL animal models have used transgenic mice expressing oncogenes known to be up-regulated in MCL, such as cyclin D1, c-Myc, and Bcl2. Lymphomas arising in these models resemble various NHL-B histotypes, but not MCL.12, 13, 14, 15, 16, 17, 18, and 19 Given the importance of an adequate animal model to study MCL and test new therapies, alternative strategies have been proposed. Xenotransplantation models have been produced in severe combined immunodeficiency (SCID) mice growing human MCL cells.20, 21, and 22 Another candidate MCL model has been created in Eμ-cyclin D1 transgenic Balb/c mice treated with 3-monthly intraperitoneal injections of the tumour promoter pristine. 23 In addition, the first animal model that spontaneously develops MCL has been described recently. 24 This model, obtained by crossing interleukin 14α transgenic mice with c-Myc transgenic mice, closely resembles the human blastoid variant of the disease. Interestingly, it lacks the t(11;14) translocation, but cyclin D1 is overexpressed, presumably by other mechanisms, again indicating that cyclin D1 appears to be necessary, but not sufficient, for mantle cell lymphomagenesis.
Expression and genomic profiling of mantle cell lymphoma
The completion of the human genome project and the development and implementation of several different microarray-based technologies have allowed the high throughput monitoring of the expression and copy number of thousands of genes in a single experiment. Several studies have been published based on the conventional CGH (comparative genomic hybridization) analysis of MCL.25, 26, 27, 28, 29, 30, 31, and 32 More recently, a few studies have used array-CGH to analyze MCL series.28, 29, 33, 34, 35, 36, 37, and 38 Supplementary Table S1 summarizes the different studies on genomic and expression profiling of MCL.
An overview of the loci detected by CGH and aCGH in MCL and the percentage of altered samples in each study are shown in Table 1 and Supplementary Table S2 . Out of 138 reported alterations, 82 correspond to losses, 55 reflect gains ( Supplementary Table S2 ) and one region has been reported to be either lost or gained. Although each platform defines different chromosomal regions, the reported alterations are similar and show the same pattern of change (gain or loss) in almost all cases. In overlapping altered regions, the incidence of the changes is similar among the different studies, validating the data and showing that those reported altered regions are consistent and may harbour important tumour suppressor genes and oncogenes. Considering those alterations that appear in more than 20% of the samples in at least two studies, we can determine that the most commonly-gained regions are: 3q, 7p, 8q24.2, 12q and the most frequently-lost regions are: 1p (inside the short arm of chromosome 1: 1p13.2–p31.1), 6q (inside the long arm of chromosome 6: 6q16.2–q27 and 6q23.2–q27), 8p, 9p, 9q, 11q (inside the long arm of chromosome 11: 11q14.3–q23.3 and 11q22.3), and 13q (inside the long arm of chromosome 13: 13q14.2–q14.3 and 13q31.3–q33.2).
|Chromosome||Cytogenetic band||% Losses||% Gains||Reference|
|1||1p13.2–p31.1||29–33||25 and 34|
|1p||24–33||26, 28, and 30|
|2||2q13||12.5–17||38 and 39|
|3||3q||30–70||25, 26, 28, 30, and 32|
|6||6q16.2–q27||31–36||34 and 38|
|6q23.2–q27||25–36||37 and 39|
|6q||27–30||26, 30, and 32|
|7||7p12.1–p22.3||18.8–29||34 and 39|
|7p||19–27||25, 26, and 32|
|8||8p21.3||17–26||34 and 36|
|8p21-pter||13–34||29 and 31|
|8p||23–33||25 and 28|
|8q24.2||16–30||26, 27, 28, 30, 32, and 36|
|9||9p||16–30||26, 27, 30, and 32|
|9q13–q31.3||18.8–31||34 and 39|
|9q||20–30||28 and 32|
|10||10p14–p15||18–20.75||26 and 29|
|11||11q13.3||9–12.5||29, 36, and 39|
|11q14.3–q23.3||22–55||26, 34, and 38|
|11q22.3||21–57||29, 36, and 37|
|11q||16–37||27, 28, 30, and 32|
|12||12q13.1–q14.1||3–15.6||36 and 39|
|12q||20–30||25 and 26|
|13||13q14.2–q14.3||25–43.8||36 and 39|
|13q31.3||5–12.5||36 and 39|
|13q31.3–q33.2||28–43||36 and 37|
|13q||33–60||25, 27, 28, 30, and 32|
|15||15q||16–26||30 and 32|
|17||17p||16–30||26, 27, and 28|
|18||18q21.33–q22.3||5–17||34, 36, and 39|
|18q||18||26 and 27|
|22||22q12.1–q12.3||19–50||37 and 38|
|22q13.31–q13.32||12.5–50||37 and 39|
The introduction of aCGH has allowed not only the confirmation of copy number changes detected with conventional CGH, but also the detection with high resolution of complex DNA alterations (e.g., regions of high level amplifications and high-magnitude deletions) likely to harbour important oncogenes and tumour suppressor genes that are often below the detection limit of conventional karyotyping and metaphase CGH. Flordal Thelander and coworkers reported homozygous deletions in 1p32.3 and 13q32.3. 34 The first deletion contains the CDKN2C locus (coding for p18INK4c), which has also been suggested to be important in MCL by other studies.35 and 39 The 13q32.2 deletion does not harbour any known tumour suppressor gene. However, other authors have found amplifications in the 13q31.1 region targeting c13orf25 gene. 40 Flordal Thelander and coworkers also found that the widely-described gain of 3q ( Table 1 ) was associated with shorter survival, 34 a prognosis indicator also described previously.26 and 31 Moreover, the loss of the 9q region has also been associated with short survival.31 and 36 The pro-apoptotic gene BIM, which is located at 2q13, has been demonstrated to be homozygously deleted in 5 MCL cell lines and in 1 Burkitt lymphoma cell line 35 and it was found to display a heterozygous loss in five MCL patients. 38 BIM is a member of the BCL2 protein family with pro-apoptotic properties. BCL2 itself, which is an anti-apoptotic member of the family, has been reported to be amplified in MCL.29, 33, 36, 38, and 39 Other genes that play a role in controlling the cell cycle or the DNA damage repair machinery such as INK4a,29, 31, and 36ATM29, 36, and 37 and TP5331 and 36 have also been reported to be altered. Interestingly, Vater et al. have recently described altered genes involved in microtubule dynamics such as MAP2, MAP6 and TP53. 39 Moreover, the same authors and others show that uniparental disomy is a frequent genetic mechanism alternative to chromosomal deletion in MCL cell lines.39, 40, and 41 The list of candidate genes is rapidly expanding and their relevant role in MCL merits further investigation.
Other studies are aimed at characterizing subgroups of the disease. The differences between cyclin D1-positive and negative tumours have been explored28 and 31 and the conclusion is that there are no differences in their genomic profiles. Other authors have investigated whether differences exist between the blastoid variant and the leukemic variant of MCL.26, 30, and 36 Some alterations are specific to the blastoid or the leukemic variant, and the blastoid variant seems to have more chromosomal aberrations than other lymphomas with typical morphology. More recently, Blenk and coworkers have compared patients with different prognosis 42 and have found suitable markers of prognosis.
Expression profiling of lymphomas has revealed that existing diagnostic categories are comprised of biologically distinct entities. In this regard, gene expression analysis has shown promising results in discriminating DLBCL (diffuse large B-cell lymphoma) subgroups into two molecular and clinically distinct disease entities. 43 Microarrays have also been applied to the study of MCL with different aims. Rosenwald et al. have defined the MCL proliferation signature which can predict the length of survival following diagnosis. 44 Cyclin D1 positive and negative MCLs can be clearly distinguished from other lymphoma types with this proliferation signature, corroborating the fact that cyclin D1-negative MCL is indistinguishable from cyclin D1-positive cases at the gene expression profile level. They suggested the use of the four most-representative genes of this signature (CDC2, ASPM, tubulin, CENP-F) as a prognostic marker. Most studies published so far compare MCL tumours with normal counterparts, although other studies focus on the differences between MCL and other lymphomas or between different variants of MCL. We have summarized the most relevant findings. Supplementary Table S1 lists the main features of the MCL profiling studies discussed in this review, and Table 2 provides an overview of the genes found to be differentially expressed between MCL samples and normal counterparts across the reports. Individual genes have been included in Table 2 if reported in at least two independent studies. In these studies, relatively small cohorts of tumours with paired controls were subjected to microarray analysis using high-density oligonucleotide, cDNA microarrays, protein microarrays and methylation microarrays. Comparative analysis of differentially-expressed genes among independent studies shows a relatively limited degree of overlap. Differences in methodology, sample selection and preparation and type of -omics platform employed are likely to explain the observed differences among these studies. Notwithstanding the latter, the genes reported in Table 2 provide broad functional categories that are roughly indicative of the biological processes altered in MCL. Interestingly, only two of the 30 genes listed appear to be downregulated, while all the rest are upregulated. Among those recurrent changes, there are five genes reported in at least three papers: CCND1 (cyclin D1), BCL2, CNN3 (Calponin 3), ENPP2 (Autotaxin) and HOMER3. The detection of cyclin D1 provides a good quality-control of these studies, since its overexpression is a hallmark of MCL.
|Gene symbol||Gene description||Chromosome localization||References||MCL vs. normal|
|AEBP1||AE-binding protein 1||7p13||139 and 140||Up|
|AHNAK||AHNAK nucleoprotein (desmoyokin)||11q12.2||45 and 67||Up|
|BCL2||B-cell CLL/lymphoma 2||18q21.3||45, 46, 47, and 48||Up|
|CCL5||Chemokine (C–C motif) ligand 5||17q11.2–q12||140 and 141||Up|
|CCND1||Cyclin D1||11q13||45, 46, 47, 64, and 140||Up|
|CNN3||Calponin 3||1p22–p21||45, 139, and 140||Up|
|CTBP2||CTBP2 (C-terminal binding protein 2)||10q26.13||64 and 67||Up|
|CYFIP1||Cytoplasmic FMR1 interacting protein 1||15q11||67 and 139||Up|
|DBN1||Drebrin 1||5q35.3||139 and 140||Up|
|ENPP2||Ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)||8q24.1||67, 139, and 140||Up|
|FARP1||FERM, RhoGEF, and pleckstrin domain protein 1 (chondrocyte-derived)||13q32.2||139 and 140||Up|
|HDGFRP3||Hepatoma-derived growth factor, related protein 3||15q25.2||67 and 140||Up|
|HOMER3||Homer homolog 3 (Drosophila)||19p13.11||67, 139, and 140||Up|
|IFI17||IFN-induced protein 17||11p15.5||45 and 46||Down|
|IL-18||IFN-γ inducing factor||11q22.2–q22.3||45 and 46||Up|
|KIAA0649||KIAA0649||9q34.3||67 and 139||Up|
|KIAA0980||KIAA0980 protein||20p11.22–p11.1||67 and 139||Up|
|L1CAM||L1 cell adhesion molecule||Xq28||45 and 64||Up|
|LAMB3||Kalinin B1||1q32||48 and 64||Up|
|MAST4||Microtubule associated serine/threonine kinase family member 4||5q12.3||67 and 139||Up|
|MDM2||MDM2 (murine double minute 2)||12q14.3–q15||46 and 64||Up|
|MSR1||Macrophage scavenger receptor 1||8p22||67 and 139||Up|
|NFE2L3||Nuclear factor (erythroid-derived 2)-like 3||7p15–p14||67 and 140||Up|
|PON2||Paraoxonase 2||7q21.3||67 and 139||Up|
|PRKCB1||Protein kinase C, beta 1||16p11.2||46 and 140||Up|
|RAB33A||Member RAS oncogene family, member of the RAB family of small GTPases||Xq25||45 and 67||Down|
|SOX11||SRY (sex-determining region Y)-box 11||2p25||67 and 139||Up|
|SPARC||Secreted protein, acidic, cysteine-rich (osteonectin)||5q31.3-q32||47 and 140||Up|
|TBP||TATA box binding protein||6p21.1||46 and 64||Up|
|TNFRSF7||Tumour necrosis factor receptor superfamily, member 7||12p13||47 and 67||Up|
BCL2 encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. It is reported to be altered in four studies.45, 46, 47, and 48 Overexpression of BCL2 has been reported in different types of non-Hodgkin’s lymphomas (NHL) by various approaches,49, 50, and 51 and it seems to be the key NFκB target that distinguishes small and aggressive B-cell lymphomas as shown recently. 52
The other genes have not been previously reported to be involved in MCL. CNN3 (Calponin 3), located at 1p22–p21, is associated with the cytoskeleton. Calponin has been related to myofibroblastic tumours. ENPP2 (autotoxin) is a secreted tumour-associated factor with lysophospholipase-D activity. Its expression is upregulated in several types of carcinomas. HOMER3 (Homer homolog 3(Drosophila) is a member of the homer family of dendritic proteins and is involved in cell growth. The study of the role of these recurrent genes in MCL could shed light into new molecular mechanisms involved in lymphomagenesis.
Molecular pathways involved in the pathogenesis of mantle cell lymphoma
The identification of new targets, together with their functional characterization within pathways controlling MCL development and progression, is crucial to design new therapeutic approaches for this disease. Most of the molecular alterations described so far target three major cellular processes: cell cycle control, DNA damage response and survival/apoptosis pathways. Here we summarize the most relevant alterations found in MCL and their functional roles, as depicted in Fig. 1 .
Cyclin D1 and cell cycle
Overexpression of cyclin D1, the hallmark alteration in MCL, accelerates the G1/S transition. Cyclin D1 binds to cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) which functionally inactivate the retinoblastoma protein (pRb) by phosphorylation, hence promoting cell cycle progression. 53 Besides cyclin D1 abnormal expression, genomic deletion of the CDKN2A locus on chromosome 9p21 is detected in aggressive MCL cases.54, 55, 56, and 57 This locus encodes two different tumour-suppressor genes: INK4a (p16INK4a, CDK4/6 inhibitor) and ARF (p53 regulator). p16INK4a inhibits CDK4 and 6, thus maintaining pRB in its active state. Cyclin D1 overexpression and INK4a deletion cooperate to promote the G1/S transition. ARF is also encoded by CDKN2A and its main function is to stabilize p53. Both the cell cycle and p53 function are altered when CDKN2A is lost, contributing with cyclin D1 overexpression to cell cycle deregulation. In cases lacking this deletion, other members of these two pathways can be altered. BMI1 amplification,44 and 58MDM2 and CDK4 amplification, 59 p53 mutation or pRb deletion 60 have also been described as alternative mechanisms in MCL pathogenesis.
DNA damage response pathway
MCL is one of the lymphomas with the highest chromosomal instability, mainly caused by defects in the DNA damage response machinery. ATM deletions are frequent in MCL due to the loss of the 11q22–23 region ( Table 1 ). ATM has a central role in response to DNA damage during the normal immunoglobulin recombination and is normally expressed in naïve B cells of the mantle zone. It encodes a protein kinase related to the PI3K family. It is believed that its inactivation can lead to chromosomal instability. 61 Other members of the DNA damage response pathways can be altered, including CHK1 and 2, which are ATM targets that have been shown to be downregulated. 62
Apoptosis and survival
Apoptosis-related genes have also been found to be altered in MCL using different approaches. The most relevant apoptotic pathway is the BCL2-system. The chromosomal region containing BCL2 is amplified in MCL resulting in overexpression of the protein, which can in turn inhibit the cytochrome C1 system and thus prevent caspase 9-mediated cell death. 63 Homozygous deletions of BIM, another member of the BCL2 family, have also been found.35 and 38 Several types of caspases2, 7, and 9 have been shown to be downregulated in different microarray studies.46, 47, and 64 NFκB and AKT signalling pathways, two crucial pathways promoting cell proliferation and survival, are constitutively activated in MCL.65 and 66 NFκB activation leads to overexpression of target genes such as FADD-like apoptosis regulator (FLIP). The AKT pathway contributes to the pathogenesis and survival in MCL66 and 67 and several members of the pathway are altered in MCL as shown by different microarray analysis. 67
The cell cycle, DNA damage and apoptosis pathways (illustrated in Fig. 1 ) converge to give rise to the pathogenic malignant phenotype. These molecular alterations might be druggable, and in this vein, preclinical and in some cases preliminar clinical studies are showing relevant activity, as discussed in the next section.
Current standard therapies in mantle cell lymphoma
Conventional CHOP regimens have been the standard treatment of MCL until the recent incorporation of Rituximab, a monoclonal antibody targeting the CD20 antigen extensively expressed in MCL cells.2, 68, 69, and 70 This incorporation, along with the use of more intense regimens, such as HyperCVAD/Metotrexate-Ara-C or combinations with other active drugs, such as FMC (fludarabine, mitoxantrone, cyclophosphamide) and others coupled to Rituximab elicit a higher complete response rate, but so far it does not translate in a meaningful increase in survival. In fact, there is no plateau observed in both PFS and OS Kaplan–Meir curves, indicating that even with those intense regimens this disease remains incurable with the current treatment approaches. Moreover, the incorporation of high dose chemotherapy supported by transplantation of haematopoietic stem cells does not offer a clear indication of improvement in survival curves.71, 72, and 73 Also, this therapeutic modality is only applied to younger and fit patients, and we need to consider the elderly population affected by this lymphoma. However, according to preliminary experience in few selected candidates, allogeneic procedures represent a promising and potentially effective salvage strategy for patients with relapsed and refractory mantle cell lymphoma.74 and 75
Approaches including anti-idiotype vaccination as well as transfer of RNA coding for co-stimulatory molecules such as CD40L and other important molecules are active research approaches in preliminary phases that obviously require mature clinical results to evaluate their therapeutic potential in this disease. 76 Interestingly, these and other procedures such as specific autologous cytotoxic T-cell transfer might be ideally suited for minimal residual disease conditions in order to control or eventually eradicate the disease leading to molecular remission.
Altogether, more specific and less toxic therapeutic modalities based on the typical molecular alterations present in this disease need to be tested. We will next discuss new therapeutic strategies based on new drugs families that target key molecular pathways of major relevance in this malignancy.
New therapeutic strategies in mantle cell lymphoma
The pharmacological inhibition of the function of a gene product known to be over-expressed or over-activated in cancer is generally referred to as a targeted therapy. This approach can be considered as equivalent to a genetic loss-of-function mutation. Examples of such drugs are the inhibitors of signalling proteins/pathways such as PI3K/AKT, IKK/NFκB, mTOR, and the inhibitors of cell cycle regulators such as the cyclin-dependent kinases (CDKs). Another variant of targeted therapeutics are agents that, despite having specific cellular targets, alter the function of many intracellular proteins and selectively induce cancer cell death by an as yet unidentified mechanism. Examples include proteasome inhibitors, histone deacetylase (HDAC) inhibitors and heat-shock protein 90 (Hsp90) inhibitors. These new agents have provided encouraging data in the treatment of various types of cancer. We will discuss herein the relevance of these new therapeutic strategies in MCL, which are illustrated in Fig. 2 . Table 3 compiles the available information regarding the efficacy of these targeted therapies in in vitro and in vivo models of MCL.
|Type of agent||Drug||Molecular target||Mechanism||Synergy||Reference|
|PI3K inhibitor||LY294002||AKT/p-AKT||Cell cycle arrest|
|AKT inhibitor||1l-6-Hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate||I κB|
|Caspase-3, -8, -9|
|mTOR inhibitor||Rapamycin||Cyclin D1||Cell cycle arrest (G1)||84|
|NFkB/IKK inhibitor||BAY 11-7082||Cyclin D1||Cell cycle arrest||TRAIL stimulators||65|
|Bax||Rituximab + Ciclophospamide||87|
|HDAC inhibitor||SAHA||Cyclin D1||Cell cycle||106|
|HSP inhibitor||Geldanamycin||CyclinD1||Cell cycle arrest||112|
|Intrinsic caspase pathway||Apoptosis|
|CDK inhibitor||Flavopiridol||Cyclin D1||Cell cycle arrest (G2/M)||117|
|Styril sulphones||p21, p27||Apoptosis||Doxorubicin Vincristine||118|
|BCL2 inhibitor||Genasense||Cyclin D1||Apoptosis||Bortezomib||103|
|Extrinsic pathway||TRAIL and derivatives||125|
|PPAR agonist||Growth inhibition|
|Vitamin A analogue||Retinoic acid||Cyclin D1||Inhibit proliferation||128|
|Impair CD40, IL-4 growth||129|
|Farnesyl transferase inhibitor||R115777||Caspase 3||Inhibit proliferation||Vincristine||132|
|TfR monoclonal antibody||A24||Caspase 3, 9||Apoptosis||Ara-C (Aracytine), VP-16 (etoposide)||137|
The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is involved in the transduction of extracellular stimuli that control many biological functions, including cell proliferation, cell survival, and insulin responses. 77 Importantly, constitutive activation of the PI3K pathway facilitates tumour formation by two different mechanisms: it supports S-phase entry, and it confers resistance to apoptotic signals which normally restrict uncontrolled cell growth. 78 Chemical inhibitors of this pathway include LY294002, Wortmannin (inhibitors of PI3K), Triciribine and SH-5 (inhibitors of AKT). Although these drugs have been widely used in in vitro models of different types of cancer including NHL, little is known about their effect in MCL.
Gene expression profiling studies with oligonucleotide microarrays have revealed the aberrant expression of genes from the PI3K/AKT pathway in purified MCL cells. 67 Genes coding for the catalytic subunit of PI3K (PI3KCA), the protein kinases PDK1 (PDPK1) or AKT1 (AKT1) show consistent overexpression in cells derived from the peripheral blood of leukemic MCL patients, when compared with their normal counterparts. In the same line of evidence, AKT is phosphorylated in aggressive blastoid MCL primary cells and cell lines, 66 and to a lesser extent in cases of typical MCL. The constitutive activation of AKT in MCL has also been correlated with expression of the inactive form of PTEN. 79 Interestingly two separate studies show that treatment of MCL cell lines with inhibitors of PI3K and AKT leads to cell-cycle arrest and apoptosis,66 and 79 and reduced telomerase activity. 79
The mammalian target of rapamycin (mTOR) is a highly conserved kinase that regulates translation of proteins important for cellular proliferation and growth. mTOR was identified based on its similarity with the yeast proteins TOR1/2, and its interaction with the immunosuppressant rapamycin when associated with the transporter protein FKBP-12. 80 Although gain of function mutations in mTOR have not been described in human cancer, its function is indirectly enhanced in several conditions associated with cancer such as loss of PTEN function and constitutional or growth factor-induced stimulation of PI3K/AKT signalling, 81 making mTOR a strong target candidate for cancer therapy.
By blocking mTOR, rapamycin is able to decrease the formation of cyclin/CDK complexes and the accumulation of p27kip1 causing a cell-cycle arrest in G1. 82 Cell cycle arrest can also be induced by inhibition of the cap-dependent translation of key proteins such as cyclin D1, 83 making this strategy very attractive for the treatment of MCL. In addition to rapamycin, several other compounds targeting mTOR are being developed such as Temsirolimus (CCI-779), Everolimus (RAD001), and Deforolimus (AP23573).
A recent study has revealed that mTOR signalling is activated in MCL tumour samples and cell lines. 84 Interestingly, this study shows that rapamycin treatment of MCL cell lines causes cell cycle arrest and apoptosis associated with down-regulation of cyclin D1 and several anti-apoptotic proteins. In a separate study, rapamycin has been reported to inhibit proliferation and reduce expression of cyclin D3 and cyclin A in MCL cell lines as well as in freshly isolated MCL cells. 85 A recent report shows that rapamycin treatment not only decreases proliferation of primary MCL cultures and cell lines, but also inhibits growth induced by CD40 and IL-4. 79 Interestingly, Temsirolimus and Everolimus show synergistic cytotoxicity with other agents such as vorinostat, 86 and Doxorubicin or Rituximab. 87
Clinical studies have also proved the efficacy of mTOR inhibitors in MCL. A phase II clinical trial concluded that Temsirolimus as a single agent has substantial antitumour activity in relapsed or refractory MCL, 88 with a response rate of 38%. Similarly, Everolimus has proven to be effective in a phase I/II trial in relapsed or refractory haematological malignancies such as MCL. 89 Recently, a phase II clinical trial of Deforolimus in relapsed and refractory haematological malignancies has shown partial responses in cases of MCL. 90
NF-κB is a ubiquitously-expressed family of transcription factors that includes p65 (RelA), p50/p105, p52/p100, c-Rel, and RelB, all of which can bind to DNA and form hetero or homodimers. Normally, NF-κB exists as an inactive complex in the cytoplasm bound to a family of inhibitors of κB (IκB). Upon cellular stimulation by specific signals, IκB is phosphorylated by the IκB kinase (IKK) complex and then degraded by the proteasome. Subsequently, NF-κB translocates to the nucleus, where it regulates the transcription of genes implicated in cell growth, survival, and adhesion processes. 91 Inappropriate activation of the NF-κB pathway has been shown to contribute to tumour formation, while increased DNA binding is associated with tumour resistance to chemotherapy. 92 Notably, NF-κB signalling has a key role in haematopoietic differentiation and several haematopoietic pathologies have been associated with deregulation of NF-κB. 93
A study in MCL cell lines and MCL patient biopsies has revealed the constitutive activation of NF-κB. 65 Furthermore, it shows that the NF-κB inhibitor BAY 11-7082 inhibits cell proliferation, decreases cyclin D1 levels and ultimately induces apoptosis of MCL cells, and that cell viability is also compromised by expression of a super-repressor form of IκB. The sensitivity of MCL cells to the TNF factor TRAIL has been linked to the activity of the NF-κB p50 factor. 94 NF-κB complex inhibitors such as BMS-345541 and BAY 11-7082 increase TRAIL cytotoxicity of several MCL cell lines, allowing MCL cells to undergo TRAIL-mediated apoptosis. These results support the use of a combination of TRAIL stimulators and NF-κB inhibitors as a new therapy for MCL.
The ubiquitin-conjugating reactions are the cell’s system of tagging or earmarking specific proteins for eventual proteolytic degradation by the 26S proteasome, an aggregate of proteolytic enzymes. It is estimated that 80–90% of all intracellular proteins are degraded by the ubiquitin-proteasome in a lysosomal-independent, and ATP-dependent manner.
Bortezomib (PS-341, Velcade) is the first of a class of drugs capable of inhibiting the 26S proteasome. Though drugs such as Bortezomib may be viewed as targeted agents, it is clear that they are associated with a huge variety of biological effects since protein degradation occurs in all cells. The rationale for the use of Bortezomib in the context of cancer treatment is based in the fact that inhibiting the proteasome can affect the NF-κB signalling pathway, increase the accumulation of proapoptotic proteins in the mitochondrial membrane, and cause a decreased degradation of CDK inhibitors such as p27kip1and p21cip1. 95 Interestingly, it has been demonstrated that MCL actually exhibits normal p27kip1 mRNA expression, but increased p27kip1 degradation. 96 Furthermore, the absence of p27kip1 in MCL is considered as a prognostic marker that identifies patients at high risk.
The in vitro sensitivity to Bortezomib has been analyzed in MCL cell lines and in primary tumour cells from MCL patients, 97 showing that exposure of MCL cells to Bortezomib activates the mitochondrial apoptotic pathway, generates reactive oxygen species (ROS) and activates the apoptotic protein Noxa. A recent report has revealed in vitro and in vivo data confirming the efficacy of Bortezomib. Bortezomib inhibits growth of MCL cell lines in a time-dependent manner, and strongly suggest enhanced efficacy if combined with cytarabine. 98 Interestingly, the same study presents two case reports which show that combining proteasome inhibition with high-dose cytarabine is feasible and highly active in MCL.
In recent years, different clinical trials with Bortezomib have been conducted in the context of MCL. A phase II clinical study revealed a significant single-agent activity in patients with different NHL, including MCL. 99 In a different phase II study, Bortezomib showed promising activity in relapsed MCL. 100 A multicenter phase II study with 155 relapsed or refractory MCL patients demonstrated the clinical activity of Bortezomib, in terms of durable and complete responses. 101 A recent study further proved the efficacy of Bortezomib in MCL patients, with a response rate of approximately 47%. 102
Similarly to the study with cytarabine described above, various other reports have shown that Bortezomib can have a synergistic effect when combined with other therapeutic agents. The pan-Bcl-2 inhibitor GX15-070 is a BH3-mimetic compound that binds to multiple Bcl-2 family members. Interestingly, it has been reported to sensitize MCL cells to low doses of Bortezomib. 103 Similarly, the mTOR inhibitor Everolimus shows synergistic cytotoxicity with Bortezomib in MCL cell lines. 87 A recent report shows a synergistic effect of Bortezomib with Rituximab and cyclophosphamide (BRC regimen) in inducing apoptosis of MCL cell lines and primary tumour cells compared with single-agent treatment, 104 and that the combination is also effective in in vivo studies in MCL-bearing SCID mice.
Histone deacetylase inhibitors
Histone acetyl transferases (HATs) and Histone deacetylases (HDACs) are two classes of enzymes that mediate the acetylation and deacetylation, respectively, of the lysine residues of the core histones. Thus, the acetylation status of the chromatin is dictated by the balance between the activities of HATs and HDACs. In general, increased histone acetylation is associated with open and active chromatin and increased transcription, while deacetylated histones are associated with condensed chromatin and transcriptional repression.
Abnormal activity of HATs and HDACs resulting in aberrant gene transcription is a phenomenon commonly observed in cancer cells, particularly leukemias and lymphomas. 105 Interestingly, HDACs can be inhibited by a variety of naturally occurring and synthetic compounds, most of which have been used in pre-clinical and clinical studies in different types of cancer, including MCL. These Histone Deacetylase Inhibitors (HDIs) include short-chain fatty acids (sodium butyrate, valproic acid), hydroxamic acid derivatives (suberoylanilide hydroxamic acid or SAHA) and cyclic tetrapeptides (depsipeptide or FK228).
A recent in vitro study with MCL cells revealed that treatment with sodium butyrate and SAHA potently inhibits cell viability and induces apoptosis in various cell lines. 106 Moreover, both HDI agents downregulate cyclin D1 levels, upregulate the cell cycle inhibitors p21cip1 and p27kip1, and inhibit the production of the angiogenic cytokine VEGF. In a previous study using a panel of lymphoid cancer cell lines including MCL, SAHA and valproic acid were also shown to act as potent antiproliferative agents. 107 Remarkably, SAHA inhibited the growth of human mantle lymphoma cells growing in immunodeficient mice, which suggests an in vivo anti-lymphoma activity. In another recent work, SAHA has not only been shown to suppress cyclin D1 translation in MCL cell lines, but also cause inhibition of the PI3K/AKT/mTOR pathway. 108
Recent clinical experience with SAHA in patients with pre-treated haematological malignancies includes cases of MCL. 109 Interestingly, evaluation of the effects of treatment with Bortezomib and SAHA on MCL has proved the synergistic cytotoxic effects of the combination of both inhibitors in MCL cell lines, 110 as shown by a strong increase in apoptosis and enhanced ROS generation.
The heat-shock proteins (Hsp) are molecular chaperones that guard against illicit interactions between other proteins. Their basal levels facilitate normal protein folding, whereas their increased expression after cellular stress is an adaptive response that enhances cell survival. Association with Heat shock protein 90 (Hsp90) is required for the stability and function of multiple mutated, chimerical and over-expressed signalling proteins that promote the growth and/or survival of cancer cells. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, AKT, HER2/Neu (ErbB2) and HIF-1α. Over the past decade, several small molecule drugs that target the molecular chaperone Hsp90 have been identified as potential anticancer agents (reviewed in 111 ). Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins. The first-in-class Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), a derivative of the natural product Geldanamycin, is currently in phase II clinical trials in various types of cancer.
Interestingly, treatment of MCL cell lines with 17-AAG has proved to induce cell cycle arrest and apoptosis. 112 These effects were accompanied by depletion of cyclin D1, CDK4 and AKT, and activation of the intrinsic caspase pathway.
Targeting the cell cycle: CDK inhibitors
In cycling cells, D-type cyclins assemble with their catalytic partners, CDK4 and CDK6, as cells progress through G1 phase. 113 As mentioned in previous sections, the most recognized function of cyclin D-CDK complexes is phosphorylation of the tumour suppressor Rb, a critical step for the completion of the cell division cycle (reviewed in 114 ). Cyclin A- and B-dependent CDKs activated later during the cell division cycle maintain Rb in a hyperphosphorylated form until cells exit mitosis and Rb is returned to a hypophosphorylated state in the next G1 phase.
CDK inhibitors are a heterogeneous group of compounds that are able to inhibit different CDK family members, most importantly those related to cell cycle progression (CDK1, CDK2, CDK3, CDK4, CDK6, and CDK7). Flavopiridol, a semi-synthetic flavonoid derived from the natural alkaloid rohitukine, is one of the best characterized CDK inhibitors. Flavopiridol was initially developed as an inhibitor of EGFR and protein kinase A (PKA). However, the compound was found to inhibit CDKs at far lower concentrations (nanomolar) than those required for EGFR/PKA inhibition. 115 A phase II study of Flavopiridol in untreated or relapsed MCL patients has revealed that it has modest activity as a single agent, is biologically active and may delay disease progression, suggesting its potential in combination with other active agents. 116
CYC202 (Seliciclib, R-roscovitine) is a purine analogue and a selective inhibitor of the CDK2-cyclin E complex, as well as CDK7 and CDK9. This agent has been tested in vitro in MCL cell lines, causing G2-M arrest and apoptosis. 117 These effects are accompanied with down-regulation of cyclin D1 and MCL-1 protein levels, possibly due to the inhibition of transcription elongation by RNA polymerase II.
Another exciting approach is provided by the Styril sulphones. These compounds are a novel family of non-ATP-competitive antineoplastic compounds that induce apoptosis in MCL cells. 118 This family of agents induces inhibition in key molecules involved in mantle cell lymphomagenesis including inhibition of CDKs such as CDK4-6. Importantly these compounds are able to restore the levels of cell cycle regulators characteristically downregulated in this disease, such as p27kip1 and p21cip1. In addition, an interesting synergism has been observed with Doxorubicin and Vincristine in vitro. 118 Hence this new family of drugs may have an important impact in the treatment of this disease on the future.
Intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis of MCL, constituting a major resistance mechanism to cytotoxic drugs. Bcl-2 is one of the key antiapoptotic factors involved in the pathogenesis of various types of lymphomas. Different neutralizing manoeuvres to inhibit Bcl-2, such as the antisense oligonucleotide Genasense (oblimersen sodium), have been tested in various lymphoproliferative syndromes with encouraging results.119 and 120 Interestingly, silencing Bcl-2 in MCL models is associated with a decrease in important cellular proteins such as cyclin D1, NF-κB or p27kip1. 121 Clinical data in MCL are now eagerly expected, as it may represent an important therapeutic modality in this disease.
Other inhibitors of antiapoptotic proteins including Bcl-2, Bcl-xl, and MCL-I are being tested. Among them small molecular weight compounds such as GX15-070, AT-101, ABT-737 and others have shown promising results in preclinical studies.103, 122, and 123 The data obtained in MCL cell lines and tumour cells is encouraging, as these agents not only induce apoptosis but also synergize with Bortezomib103 and 123 and several cytotoxic agents. 122
Initial experience in haematological malignancies with compounds that target the extrinsic pathway such as TRAIL and derivatives that target the DR4 and DR5 receptors of TRAIL are ongoing with robust preclinical support. 124
The Peroxisome proliferator-activated receptor gamma (PPAR-γ) protein which is highly expressed in MCL cell lines is arising increasing interest. 125 PPAR-γ is a nuclear receptor and transcription factor that characteristically interacts with jun and NF-κB transcription factors preventing them from binding to their response elements. After binding with its ligands PPAR-γ promotes considerable apoptosis in MCL cell lines. The thiazolidinediones compounds are agonist ligands of PPAR, some of them such as proglitazone and rosiglitazone have been developed as antidiabetic agents. Its preclinical and clinical development in MCL is currently ongoing. 125
Other agents: thalidomide, retinoic acid, farnesyl transferase and PKC inhibitors
Thalidomide is an immunomodulatory drug with a variety of cellular effects such as modulation of cytokine secretion, activation of T, NK and denditric cells, angiogenesis and NF-κB inhibition. It has been proven effective in haematological diseases, and two cases of relapsed refractory MCL successfully treated with thalidomide have been reported. 126 Furthermore, the combination of thalidomide plus Rituximab has proved to be effective in patients with relapsed or refractory MCL. 127
Retinoids are a group of vitamin A analogues that exert profound effects on a wide array of physiologic processes, including embryonic morphogenesis, visual response, reproduction, growth, cell differentiation, and immune function. Retinoids have been shown to inhibit the growth of transformed cells through direct modulation of the levels of cell cycle regulatory proteins. Notably, these compounds have been reported to interfere with cell cycle regulation by enhancing cyclin D1 proteolysis. 128 Interestingly, retinoic acid isomers inhibit the proliferation of primary MCL cells and MCL cell lines, 129 and impair the growth-promoting effects induced by CD40 and IL-4.
Many eukaryotic proteins, including small GTPases, co-chaperones, membrane-associated proteins, and mitotic proteins are post-translationally modified by the addition of a farnesyl group. This enzymatic process, catalyzed by farnesyl transferase (FT), is targeted by a family of anticancer agents known as the FT inhibitors (FTI). FTIs show potent cytotoxicity as a single agent in preclinical studies, 130 and have shown clinical promise in combination with other therapeutic strategies such as Bortezomib. 131 The cytotoxic activity of the FTI R115777 has been recently evaluated in MCL cell lines and nude mice, and the results obtained show that R115777 inhibits cell growth and cell viability and induces apoptosis in vitro, displaying cytostatic activity on tumour xenografts in vivo. 132 Interestingly, R115777 also increases the cytotoxicity of several agents in MCL cell lines. 132
Protein kinase C beta (PKCβ) is the major PKC isoform involved in B-cell receptor signalling, enhances B-cell proliferation and survival and is also an important modulator of the angiogenic activity of vascular endothelial growth factor (VEGF), which may enhance tumour angiogenesis in lymphoid malignancies. 133 Immunohistochemical studies have shown that PKCβ is expressed in 90% of all MCL samples, 134 indicating that PKCβ could be a rational target in MCL since inhibition of PKCβ may impact both the microvasculature and tumour cell growth. Enzastaurin is an acyclic bisindolylmaleimide that was initially developed as an ATP-competitive, selective inhibitor of PKCβ and that also happens to inhibit signalling through the PI3K/AKT pathway. 135 Interestingly, a phase II study in 60 patients with relapsed or refractory MCL has shown progression-free survival in 10% of patients and a favourable toxicity profile, 136 indicating that Enzastaurin could be evaluated as maintenance and/or combination therapy in MCL.
Prevention of MCL establishment by routing the transferrin receptor toward intracellular lysosomal compartments has been shown in an in vitro model. 137 In fact this is an interesting approach that merits further clinical studies for rapidly growing tumour cells such as some MCL forms. Transferrin receptors are highly expressed in rapidly growing tumours including MCL but not in their normal counterparts. These tumours require transferrin for growth and survival. Therefore, impairing the function of these iron uptake receptors promotes apoptosis, and the activation of caspase 3 and 9 has been reported to account for this effect. 137 A correlation between expression of transferrin membrane receptor and Ki-67 has also been reported, 137 suggesting that this protein could represent an interesting target. The implementation of this new therapeutic modality is favoured even further by the fact that synergism with active cytotoxic drugs in MCL has been found, such as ara-C (Aracytine) or VP-16 (Etoposide). 137 It has also been reported that the transferrin receptor gene is up-regulated in MCL relapses. 138 Accordingly, multiple therapeutic avenues can be envisioned including the design of radioimmunoisotypes, or coupling of monoclonal antibodies targeting this receptor with cytotoxic agents.
The elucidation of the signal transduction network that drives neoplastic transformation has led to rationally designed cancer therapies that target specific molecular events. The emergence of tumour-specific, molecularly targeted agents signifies a paradigm shift in cancer therapy. The diversity of targets giving rise to this new generation of anticancer drugs is constantly expanding, but as highlighted here, some emerging agents are already producing significant results in both in vitro and in vivo models of human cancers, including MCL ( Table 3 ). These encouraging results provide a rationale platform for the design of new therapeutic treatments, although the efficient translation of these into the clinical practice will require continued research efforts.
Conflict of interest statement
The authors acknowledge funding from Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain (PI060371 to S.F.de M., P.V. and J.R.), Programa “Ramón y Cajal”, Ministerio de Ciencia e Innovación (S.F.de M. and P.V.), Direcció General de R+D+I, Govern Balear (PROGECIB-12A to S.F.de M. and P.V.), Junta de Balears-AECC (A.O.-H., S.F.de M. and P.V.) and Fundació Internacional Josep Carreras-Fundación Caja Madrid (FIJC-08/ESP-FCAJAMADRID to A.O.-H.).
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a Cancer Cell Biology Group, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Crta Valldemossa km 7.5. E-07122 Palma, Illes Balears, Spain
b Hospital Universitario Gregorio Marañón, Oncology Department, Dr Esquerdo, 46. E-28007 Madrid, Spain
Corresponding authors. Address: Cancer Cell Biology Group, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Crta Valldemossa km 7.5. E-07122 Palma, Illes Balears, Spain. Tel.: +34 91 5868000; fax: +34 91 5868018 (J. Rodríguez), tel.: +34 971 173004; fax: +34 971 259501 (S. Fernández de Mattos).
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