Lin Foma

1030 Current Cancer Drug Targets, 2011, 11, 1030-1043

1873-5576/11 $58.00+.00 © 2011 Bentham Science Publishers

Antiangiogenic Therapies in Non-Hodgkin's Lymphoma

J. Ruan*

Center for Lymphoma and Myeloma, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, USA

Abstract: The tumor microenvironment is critical in the initiation and progression of cancerous growth, which is

dependent on the establishment of a functional vascular network supporting neoplastic proliferation. While the precise

role of tumor angiogenesis in lymphoma pathogenesis remains under active investigation, emerging data on the pro-

angiogenic properties of the neoplastic lymphoma cells and mechanism of vascular assembly suggest that angiogenesis is

highly relevant to the biology and therapy of non-Hodgkin’s lymphoma. Antiangiogenic therapies in non-Hodgkin’s

lymphoma are in various stages of clinical development aiming at distinct angiogenic pathways operative in endothelial

cells and perivascular stromal cells. The major classes of available antiangiogenics include anti-VEGF, small molecule

inhibitors targeting proangiogenic receptor tyrosine kinases and their downstream signal transduction pathways, as well as

immunomodulatory compounds with antiangiogenic properties. Preliminary clinical data indicate therapeutic advantages

associated with strategies targeting dual compartments of vascular cells and tumor cells, as well as multiple angiogenic

pathways within the tumor microenvironment. This review summarizes recent applications of antiangiogenic strategies in

non-Hodgkin’s lymphoma based on current understanding of the biology of lymphoma angiogenesis.

Keywords: Angiogenesis, antiangiogenic therapy, microenvironment, non-Hodgkin’s lymphoma, VEGF.

INTRODUCTION

Lymphoma is the second fastest growing adult malignancy in incidence in North America. In 2010, over 65,000 new cases of non-Hodgkin’s lymphoma (NHL) were diagnosed, and more than 20,000 people died from the diseases in the US [1]. Despite the fact that multi-modality treatment including combination chemotherapy, radiation, and target-specific monoclonal antibodies can induce a high-rate of remission in many subtypes of non-Hodgkin’s lymphoma, a significant proportion of patients relapse with incurable disease [2-3]. Novel therapeutic strategies are being actively explored to overcome treatment resistance. Amongst them, anti-angiogenics has emerged as a promising treatment modality that targets tumor microenvironment in complementary to tumor cell oriented therapy.

Angiogenesis, the growth of new blood vessels, requires dynamic expansion, assembly and stabilization of vascular endothelial cells in response to pro-angiogenic stimuli. Many aspects of tumor angiogenesis have been extensively studied in the context of nonhematopoietic neoplasms in the past three decades [4-5], and anti-angiogenic strategy has become an important treatment option for solid tumors in various clinical settings including metastatic colorectal, lung, breast, renal and liver cancers [6-10]. Non-Hodgkin’s lymphoma consists of a collection of complex disease subtypes driven by monoclonal proliferation of malignant B- or T-cells, which display a spectrum of clinical behaviors, ranging from indolent subtypes with growth latency measured in years to aggressive subtypes with progression measured in weeks to months [11]. The precise role of angiogenesis in the pathogenesis of lymphoproliferative disease is under active

*Address correspondence to this author at the Division of

Hematology/Oncology, Department of Medicine, Weill Cornell Medical

College, 1300 York Avenue, Room A-605A, New York, NY 10065, USA;

Tel: 646-962-2068; Fax: 646-962-1605; E-mail: [email protected]

investigation. Emerging evidence, analyzing both the angiogenic properties of the neoplastic cells as well as vascular microenvironment, suggests divergent angiogenic patterns in disparate lymphoma subtypes. To date, several lines of evidence have pointed to the relevance of angiogenesis to lymphoma progression and clinical outcome. First, increased production of proangiogenic growth factors by lymphoma tumor cells as well as infiltrating stromal cells, and increased angiogenesis activity (by vessel counts) has been observed with histological progression of the lymphomas [12-14]. Secondly, expression of both vascular endothelial growth factor (VEGF) and VEGF receptors by the tumor cells in a number of lymphoma subtypes suggests autocrine and paracrine pro-angiogenic survival mechanisms. Thirdly, large-scale gene expression studies in follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) have demonstrated that genetic signatures expressed by stromal and infiltrating immune cells define distinct prognostic groups [15-16], with increased angiogenic activity associated with inferior outcome in DLBCL. Experimentation with anti-angiogenic strategies has shown early promise in selected subtypes. This review summarizes recent applications of antiangiogenic strategies in non-Hodgkin’s lymphoma based on current understanding of the biology of lymphoma angiogenesis.

BIOLOGY OF LYMPHOMA ANGIOGENESIS

Contribution of Tumor Microenvironment

In addition to neoplastic cells, the tumor mass is composed of a variety of interacting cell types and soluble mediators, notably the immune / inflammatory cells of hem-atopoietic origin, fibroblasts / myofibroblasts of mesen-chyaml origin, vascular endothelial cells and pericytes / vascular smooth muscle cells, as well as extracellular matrix proteins and a multitude of cytokines and growth factors which collectively form the tumor stroma [17]. The

Antiangiogenic Therapies in Non-Hodgkins Lymphoma Current Cancer Drug Targets, 2011, Vol. 11, No. 9 1031

compositions of tumor stroma evolve in response to the genetic and epigenetic programming of the neoplastic cells, while the biological behaviors of the tumor cells are reciprocally modulated by the stromal microenvironment.

The stromal microenvironment is essential for angiogenesis regulation. In normal lymph nodes, immune responses are accompanied by dramatic increases in the nodal vascularity [18]. Fibroblast-type reticular stromal cells (FRC) in the T zone and medullary cords are important VEGF-expressing cells in lymph nodes to initiate hyperplastic vascular responses [19]. It has been shown that activated B- and T-lymphocytes [20-21], as well as infiltrating CD11b

+ myelomonocytic cells [22] and CD11c

+

dendritic cells [23] can promote angiogenesis through the production of pro-angiogenic growth factors such as VEGF, and matrix metalloproteinases to support endothelial proliferation [22-28]. Trafficking of the immune cells, which express CXCR4 chemokine receptor, appears to be modulated in part by SDF-1 (CXCL12) produced by stroma surrounding high endothelial venules and lymphatic vessels [29-30].

Lymphoma microenvironment has been increasingly recognized to influence neoplastic progression and growth. In follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), large-scale gene expression profiling studies demonstrated that genetic signatures expressed by stromal and infiltrating immune cells define distinct prognostic groups [15-16]. In FL, the immune-response signature expressed largely by infiltrating non-tumor monocytes and dendritic cells predicted inferior clinical outcome [15, 31]. High amounts of intratumoral lymphoma-associated macrophages (LAM) have been shown to correlate with poor prognosis in FL patients treated with chemotherapy alone, although rituximab therapy appears to circumvent the unfavorable outcome associated with high LAM [32-33]. Increased hematopoietic infiltration by myeloid progenitors and monocytes has been correlated with histologic progression of lymphoma subtypes, suggesting that hemangiogenesis may reflect an angiogenic switch and the development of a pro-angiogenic phenotype [13, 31, 34]. In diffuse large B-cell lymphoma, distinct stromal molecular signatures have been shown to correlate with survival [35]. Specifically, “stromal-1” signature with genes enriched for extracellular-matrix deposition and histiocytic infiltration has been associated with favorable outcome. By contrast, “stromal-2” signature with genes enriched for endothelial cells and angiogenesis regulation appears to be associated with increased tumor blood vessel density and inferior clinical outcome. The precise molecular mechanisms whereby stromal cells regulate lymphoma angiogenesis remain to be clarified. The following sections attempt to provide an overview of the current understanding of the molecular mechanisms of angiogenesis regulation in the context of lymphoproliferative diseases.

Expression of Pro-Angiogenic Growth Factors

Vascular Endothelial Growth Factor / VEGF Receptors

The most important mediator of the angiogenic switch is vascular endothelial growth factor (VEGF) [36-37], a member of the VEGF family. VEGF-A (VEGF) is produced

by a variety of tumor cells as well as certain tumor-associated stromal cells [38-39], and binds to two related receptor tyrosine kinases, namely, VEGFR-1 and VEGFR-2 [37]. VEGFR-2 is the primary receptor transmitting mitogenic VEGF signals in endothelial cells, by activating both the Raf-Mek-Erk [40] and the phosphatidylinositol (PI)-3 kinase-Akt pathways [41]. VEGFR-1 regulates VEGF signaling on vascular endothelium in a tissue-specific manner [25, 37]. VEGFR-1 is also expressed on hematopoietic cells, where it mediates VEGF-directed monocyte chemotaxis, hematopoiesis and recruitment of endothelial progenitors [42]. Binding of VEGFR-1 to placental growth factor (PlGF), a homolog of VEGF, can lead to intermolecular transphosphorylation of VEGFR-2, thereby amplifying VEGF-driven angiogenesis through VEGFR-2 [43]. In addition to mediating sprouting angiogenesis, VEGF-A is essential for postnatal vasculogenesis by mobilizing both VEGFR-1

+ hematopoietic

progenitors and VEGFR-2+ endothelial progenitors from the

bone marrow [24]. The latter can differentiate and incorporate into the growing tumor neovasculature. VEGF-C and VEGF-D are primarily involved in lymphangiogenesis via interaction with VEGFR-3 in addition to VEGFR-2 in the adult [37]. VEGFR-3 signaling is required for both developmental and pathological tumor angiogenesis. Genetic targeting of VEGFR-3 or blockade of VEGFR-3 signaling with monoclonal antibodies leads to synergistic inhibition of tumor angiogenesis when used in combination with an anti-VEGFR-2 strategy [44].

VEGF gene expression is regulated by the concerted action of the transcriptional factor hypoxia-induced factor (HIF)-1 and von Hippel–Lindau (VHL) tumor suppressor gene in response to tissue hypoxia [45]. Under normoxic conditions, the VHL protein targets HIF-1 for ubiquitination and proteasome degradation. Inactivation of VHL leads to HIF-1 accumulation and VEGF upregulation in pathological conditions. Positive regulators of the HIF-1/VEGF axis include growth factors, such as basic fibroblast growth factor, transforming growth factor (TGF)- , TGF- , insulin-like growth factor 1, hepatocyte growth factor (HGF); proinflammatory cytokines such as tumor necrosis factor- , interleukin (IL)-8, IL-1 and IL-6[46]; inactivation mutations of tumor suppressor genes including VHL, p53 and PTEN [45, 47-48]; and activating mutations of proto-oncogenes such as mutant ras, c-Myc, erbB-2/Her2, bcr/abl, and B-Raf [49-54]. AKT, a central signaling molecule downstream of several important signaling pathways including PI3K, PTEN, and Ras, transmits upstream signals from growth factors, cytokines, and oncogenes [55]. Activated AKT has been shown to be necessary and sufficient to regulate VEGF and HIF-1 expression.

VEGF expression by neoplastic cells has been demonstrated in aggressive subtypes of human lymphoma including peripheral T-cell lymphomas (PTCL) [56], angioimmunoblastic T-cell lymphoma [57], diffuse large B-cell lymphoma (DLBCL) [58-59], mantle cell lymphoma (MCL) [60], primary effusion lymphoma [61], and indolent histologies such as chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL/SLL) [62-63]. In contrast, only a minority of indolent follicular lymphoma cases show variable expression of VEGF [64-65]. Increased VEGF

1032 Current Cancer Drug Targets, 2011, Vol. 11, No. 9 J. Ruan

expression has been associated with areas of transformation from indolent B-cell lymphoma to aggressive DLBCL, and poor prognostic subgroups within DLBCL [66]. Tumor cell mediated VEGF production and increased angiogenesis have been directly linked to oncogenes such as c-Myc in murine model of Burkitt’s lymphoma [67] and B-Raf in human primary effusion lymphoma [54]. Serum VEGF levels have been shown to be inversely correlated with event-free survival in NHL patients treated with chemotherapy [68].

In addition to VEGF, VEGF receptors are expressed by a number of lymphoma cells, particularly CLL and aggressive NHL subtypes, implicating VEGF-mediated autocrine and paracrine survival mechanisms [56, 69-70]. Blockade of VEGFR-1 and VEGFR-2 reduces tumor growth of human lymphoma xenografts in NOD-SCID mice [70]. VEGF signaling via VEGFR-1 and VEGFR-2 in CLL cells confers resistance to apoptosis and promotes survival [71]. Disruption of this autocrine pathway in CLL by epigallocatechin-3-gallate (EGCG), a receptor tyrosine kinase (RTK) inhibitor, leads to apoptosis and cell death. In DLBCL, VEGF expression in lymphoma cells has been shown to correlate with the expression levels of VEGFR-1 and VEGFR-2 in de novo DLBCL lymphoma cells based on immunohistochemical evaluation of tissue microarrays, raising the possibility of VEGF as an autocrine/paracrine growth factor for DLBCL cell survival and proliferation [58-59]. Analysis of genetic polymorphisms of VEGF and VEGFR2 in patients with DLBCL treated with R-CHOP therapy in Korea showed that VEGFR2 rs1870377 TT genotype was significantly

associated with adverse OS and

PFS, suggesting that differential binding of VEGF to VEGFR2 may modulate angiogenic activity and disease progression in DLBCL

1. Expression of both VEGF and

VEGF receptors has also been characterized in MCL cells [60, 72-73]. These studies collectively provide a rationale for targeted therapy against VEGF / VEGFR axis in selected NHL subtypes.

Non-VEGF Signaling Pathways

Complementary to VEGF signaling pathways, several other pro-angiogenic growth factors and chemokines participate in the elaborate regulation of angiogenic switch. The platelet-derived growth factor (PDGF) family is indispensible for its role in vascular remodeling and maturation during development and in pathological conditions [74-75]. In particular, PDGF-BB (a ligand of PDGFR- ) produced by endothelial cells recruits pericytes and promotes vascular stability and maturation [76]. Inhibition of PDGFR- signaling renders tumor vasculature particularly susceptible to VEGF withdrawal [77]. PDGF signaling also appears to be important to modulate the expression of other angiogenic factors in tumor stroma, such as basic fibroblast growth factor (bFGF) and VEGF [78-79]. PDGF-mediated PDGFR activation leads to stromal VEGF production in bone marrow mesenchymal stromal cells obtained from CLL patients [80]. The chemokine SDF-1 expression is expressed by stromal cells in lymph nodes,

1Kim, M. K.; Suh, C.; Chi, H. S.; Cho, H. S.; Lee, K. H.; Lee, G.-W.; Kim, I.-S.; Eom,

H. S.; Kong, S.-Y.; Bae, S. H.; Ryoo, H.-M.; Mun, Y.-C.; Chung, H.; Hyun, M. S.

VEGFA and VEGFR2 genetic polymorphisms and survival In patients with diffuse

large B cell lymphoma. ASH Annual Meeting Abstracts, 2010, 116 (21), 994.

bone marrow and blood [81-83]. Its receptor CXCR4 mediates homing and survival of lymphocytes, and is expressed in both normal and malignant B-cells in addition to hematopoietic progenitors [84]. SDF-1 has been shown to promote tumor angiogenesis by recruitment of vasculogenic CXCR4

+ endothelial progenitors (EPCs) from

the bone marrow [85]. It is conceivable that compounds targeting signaling pathways of alternative pro-angiogenic factors / chemokines including PDGF-BB / PDGFR and SDF1 / CXCR4 could have synergistic anti-stroma and anti-tumor activities.

Regulation of Neovascular Assembly

New vessel growth and maturation are highly complex and coordinated processes, requiring sequential and concerted participation of endothelial cells and perivascular accessory cells in response to pro-angiogenic signals within the tumor microenvironment. Both endothelial cells and pericytes represent potential targets for antiangiogenic therapy.

Endothelial Cells

Tumor endothelial assembly involves at least two principal processes. The first builds on the sprouting and co-option of pre-existing vessels mediated by the migration and proliferation of mature endothelial cells. The second is the recruitment of bone marrow derived circulating endothelial progenitors cells (EPCs) in response to pro-angiogenic signals [24, 86]. Multiple studies have addressed the roles of EPCs in tumor angiogenesis in mouse models, using myeloablative transplantation techniques which facilitated the temporal and spatial tracking of genetically marked donor bone marrow cells in the recipients. Great variance of bone marrow dependence was reported, ranging from negligible [87] to moderate (1.5% - 58%) [88-90], likely reflecting angiogenic responses to different tumor types, organ sites, and mouse strains [90]. Bone marrow-derived VEGFR2

+ EPCs appeared to incorporate into a significant

proportion of tumor neovessels (>90%) in a murine xenograft model of aggressive B-cell lymphoma in the angiogenesis-defective Id-mutant mice reconstituted with wild type bone marrow [91]. In a pilot study of six human patients with spontaneous cancers following bone marrow transplantation from opposite sex donors, an average of 4.9% bone marrow endothelial contribution was noted, with Hodgkin’s lymphoma exhibiting the greatest bone marrow component at 12.1% [92]. Another study examined the lymphoma-specific cytogenetic alterations in endothelial cells isolated from B-cell lymphomas, which showed that on average 37 percent of the microvascular endothelial cells in the B-cell lymphomas harbored lymphoma-specific chromosomal translocations [93]. Their findings raise the provocative possibility that bone marrow cells participation in the vascular assembly, and that a proportion of the lymphoma endothelial cells may derive from lymphoma-specific hematopoietic tumor stem cell / progenitors in the bone marrow.

Circulating endothelial cells and VEGF levels appear to correlate with tumor volumes in SCID mice bearing human lymphoma [94]. Igreja and colleagues have characterized CD133

+CD34

+VEGFR-2

+ EPC present in peripheral blood


and lymph nodes in patients with NHL. They found increased circulating EPCs in younger patients and those with aggressive lymphomas. The levels of EPCs decreased following complete response to treatment. In addition, lymph node-associated EPCs were detected in vascular structures and in stroma, and correlated with lesion size and increased angiogenesis in indolent lymphoma [95]. The association of circulating endothelia and EPCs with angiogenesis and lesion size provides potentially useful endothelium-specific biomarkers to evaluate the treatment response following anti-angiogenic therapy.

Perivascular Cells

In addition to endothelial cells, both hematopoietic myeloid cells and mesenchymal vascular mural cells have been shown to be important participants in the neo-vascular assembly process by providing proangiogenic growth factors such as VEGF-A, VEGF-C/VEGF-D, BDNF, PDGF, and MMP-9 [24], as well as structural guidance and support to the nascent endothelial structure [22, 96-97]. Co-recruitment of wild type VEGFR1

+ pro-angiogenic myelomonocytic

cells and their perivascular association with neovessels were essential to restore murine B6RV2 lymphoma angiogenesis in the angiogenesis-defective Id-mutant mice [91]. When the hematopoietic progenitor cells were genetically targeted and eliminated in a tumor model, neo-angiogenesis and tumor growth were both strongly inhibited, underscoring the vital contribution of pro-angiogenic hematopoietic progenitors [87, 98]. In human subjects, lymphoma-associated macro-phages (LAM) have been implicated in aggressive disease and inferior outcome in follicular lymphoma [31]. In parallel, NG2

+ and -SMA

+ pericytes / vascular smooth

muscle cells can be recruited which then differentiate and proliferate into perivascular stromal cells along with vascular endothelial cells under pro-angiogenic stimuli, such as PDGF-BB [76, 99-100]. Coverage by pericytes has been proposed as one of the key events during vessel maturation [77]. Nascent blood vessels with minimal pericyte coverage have been shown to be more sensitive to VEGF inhibition, arguing for concerted anti-pericytic strategy in order to achieve synergy with anti-VEGF therapy. Human non-Hodgkin’s lymphomas have been shown to have distinct perivascular patterns in disparate subtypes [34]. In aggressive subtypes of Burkitt’s lymphoma and DLBCL, VEGF-producing CD68

+VEGFR1

+ myelomonocytic hema-

topoietic cells were closely associated with neovessels, lending structural and paracrine support to nascent vasculature which was largely devoid of -SMA

+ pericyte

coverage in response to rapid neoplastic growth. In contrast, the perivascular compartment in indolent CLL/SLL is marked by diffuse -SMA

+ pericytic coverage, leading to a

more mature vascular composition. Thus, perivascular acce-ssory cells in lymphoma subtypes reflect differential angiogenic responses to distinct proangiogenic growth factor/cytokine milieu within the tumor microenvironment, providing potentially unique targets for anti-angiogenic intervention.

Collectively, these studies demonstrate the importance and clinical relevance of neo-angiogenesis in the pathogenesis of lymphoproliferative disease, lending support to further exploration of angiogenic mechanisms and novel anti-angiogenic therapeutics in specific lymphoma subtypes.

ANTI-ANGIOGENIC THERAPY IN HUMAN LYM-PHOMA

Although conventional maximal tolerated dose (MTD) chemotherapy can cause direct cytotoxicity on the endothelia, their effects are non-selective [101]. Certain MTD chemotherapy can potentially increase the production of tissue SDF-1 , and promote the acute mobilization and recruitment of bone marrow-derived EPCs, leading to rebound tumor neo-angiogenesis [102-103]. Therefore, the principals of antiangiogenic therapy aim at effective blockade of major angiogenic pathways operative in tumor angiogenesis, while minimizing rebound angiogenesis. A growing list of anti-angiogenics is now available, either in various stages of clinical development or as components of standard clinical regimens. The major classes of anti-angiogenic therapy include 1) direct anti-VEGF (bevacizumab, VEGF-Trap, VEGF-antisense); 2) receptor tyrosine kinase inhibitors targeting receptor signaling of pro-angiogenic factors including VEGF; 3) immunomodulatory compounds with anti-angiogenic properties; 4) anti-endothelial approach of metronomic therapy, and 5) compounds targeting signal transduction checkpoints downstream of pro-angiogenic growth factors, which include mTOR inhibitors, HDAC inhibitors, and proteasome inhibitors. Preliminary clinical evidence has been reported on the safety, feasibility and clinical efficacy of anti-angiogenic therapy in various human lymphoma subtypes, including DLBCL, CLL, MCL and peripheral T-cell lymphoma (Table 1).

Anti-VEGF Strategies

The humanized monoclonal antibody bevacizumab is the prototypic anti-angiogenic agent which targets VEGF-A [104-106], thereby disrupting VEGF-mediated autocrine and paracrine survival mechanisms. When used in combination with chemotherapy, bevacizumab improves progression-free survival in humans with metastatic colorectal, renal, breast, and advanced non-small cell lung cancer [6-9].

In Southwestern Oncology Group (SWOG) S0108 study, bevacizumab (Avastin

TM, Genentech and Roche) has shown

limited clinical activity (25% disease stabilization) as a single agent in lymphoma patients with relapsed aggressive NHL when administered at 10 mg/kg every 2 weeks [72]. Bevacizumab has been combined with rituximab-CHOP in upfront treatment. Ganjoo and colleagues reported the safety and clinical efficacy of a pilot study with bevacizumab plus R-CHOP in 13 patients with untreated DLBCL[107]. Bevacizumab was administered through a central line at 15 mg/kg on day 1 followed by R-CHOP on day 2 for cycle 1 and day 1 for cycles 2 – 8. An overall response rate of 85% and a complete response rate of 38% were demonstrated with 12-month progression free survival (PFS) of 77% at the time of reporting, in line with efficacy expected for R-CHOP therapy. There appeared to be a marginal correlation between the baseline plasma VEGF-A level and response to treatment. No significant toxicity was reported. Subsequent phase II and phase III efficacy studies evaluated the combination of bevacizumab plus R-CHOP in first line setting for aggressive NHL. The Phase II SWOG S0515 study enrolled 64 patients with advanced stage DLBCL who


Table 1. Summary of published anti-angiogenic therapy in NHL.

Agents Disease Phase Sample

size

ORR CR PR Response

Duration

PFS OS Referen

ce

Bevacizumab DLBCL/

MCL

II 52 2% 0 2% 5.2 months 16% @6

months

53% @ 6

months

[72]

Bevacizumab

+ R-CHOP

DLBCL II 13 85% 38% 46% NR 77% @1 yr NR [107]

Bevacizumab

+ R-CHOP

DLBCL II 64 NR NR NR NR 77% @ 1 yr

69% @ 2 yr

86% @ 1 yr

79% @ 2 yr

Footnoteb

Anti-VEGF

VEGF-AS NHL I 7 14% NR 14% NR NR NR [108]

Thalidomide Indolent

NHL

II 24 12.5% 8% 4% 5.4 months 29% @ 1 yr 24.8 months [118]

T+F CLL I 13 100% 55% 45% NR NR NR [119]

T+F CLL II 16 31% 6% 25% NR NR NR Footnotec

T+R MCL II 16 81% 31% 50% NR 20.4 months 75% @ 3 yr [120]

Lenalidomide Aggressive

NHL

II 49 35% 12% 23% 6.2 months 4 months NR [121]

Lenalidomide Aggressive

NHL

II 217 35% 13% 22% 10.6 months 3.7 months NR [122]

Lenalidomide Indolent

NHL

II 43 26% 7% 19% > 16.5

months

4.4 months NR [123]

Lenalidomide MCL II 15 53% 20% 33% 13.7 months 5.6 months NR [124]

Lenalidomide PTCL II 24 30% 0 30% NR 96 days 241 days [125]

Lenalidomide CLL II 45 47% 9% 38% NR 81% @ 1 yr NR [126]

Lenalidomide CLL II 35 33% 5% 28% NR NR NR [127]

L+R MCL I/II 36 53% 31% 22% 18 months 14 months NR Footnoted

iMiDs

L+R Indolent

NHL

II 30 86% 79% 7% NR NR NR Footnotee

Celecoxib

+Cytoxan

Aggressive

NHL

II 35 37% 6% 31% 8.2 months 4.7 months 14.4 months [130]

PEPC NHL NA 75 69% 36% 33% NR NR NR [131]

PEPC MCL NA 22 82% 46% 36% NR NR NR [132]

Metronomic

RT-PEPC MCL II 22 73% 32% 41% NR 10 months NR [73]

Temsirolimus MCL II 34 38% 3% 35% 6.5 months 6.9 months 12 months [137]

Temsirolimus MCL III 162 22% 2% 20% NR 4.8 months 12.8 months [138]

Temsirolimus NHL:

DLBCL

FL

CLL/SLL

II 89

28.1%

53.8%

11%

12.5%

25.6%

0

15.6%

28.2%

11%

NR

NR

NR

2.6 months

12.7 months

NR

7.2 months

Not reached

NR

[139]

Aggressive

NHL

II 77 30% 4% 26% 5.7 months NR NR [140]

CLL II 22 18.2% 0 18.2% NR NR NR [141]

mTORi

Everolimus

WM II 50 70% 0 PR 42%

MR

28%

Not reached 75% @6

mon

62% @1 yr

Not reached [142]


(Table 1). Contd.....

Agents Disease Phase Sample

size

ORR CR PR Response

Duration

PFS OS Reference

Vorinostat CTCL IIb 74 29.7% 1.3% 28.4% 185 days 4.9 months NR [148]

Vorinostat CTCL II 33 24% 0 24% 15.1 wks 30.2 wks NR [149]

Vorinostat DLBCL II 18 5.6% 0 5.6% 44 days NR NR [150]

Romidepsin CTCL II 71 34% 6% 28% 13.7 months NR NR [151]

Romidepsin CTCL II 96 34% 6% 28% 15 months NR NR [152]

Panobinostat CTCL I 10 60% 20% 40% 179 days NR NR [153]

HDACi

MGCD0103 NHL II 50 10% 2% 8% NR NR NR Footnotef

Bortezomib Indolent

NHL/MCL

II 26 58% 12.5% 46% NR NR NR [158]

Bortezomib MCL II 33 41% 20.5% 20.5% NR NR NR [159]

Bortezomib MCL II 155 33% 8% 26% 6.2 mon 9.2 months 69% at 1

yr

[160]

Bortezomib MCL II 30 46.4% 3.6% 43% NR 10 months NR [161]

Proteasome

inhibitors

Bortezomib WM II 27 26% 0 26% NR NR NR [162]

Abbreviations: NHL-non Hodgkin’s lymphoma; VEGF-vascular endothelial growth factor; R-rituximab; AS-anti-sense; T-thalidomide; F-fludarabine; L-lenalidomide; PEPC-

prednisone, etoposide, procarbazine, cyclophosphamide; iMiDs-immunomodulatory drugs; mTORi-mammalian target of rapamycin inhibitors; HDACi-histone deacetylase inhibitors;

WM-Waldenstrom macroglobulinemia

NR-not reported; NA-not applicable, retrospective chart review

ORR-overall response rate; CR-complete response; PR-partial response; MR-minimal response; PFS-progression-free survival; OS-overall survival; yr-year; wk-week.

received bevacizumab at 15 mg/kg on day 1 with standard R-CHOP

2. The estimated 2-year PFS and overall survivals

were comparable to historical projection for R-CHOP alone, while significant toxicities associated with bevacizumab were observed including sudden death, GI perforations, grade 3/4 thrombotic events, and grade 2/3 left ventricular dysfunction. Although preliminary, bevacizumab plus R-CHOP combination appears to fall short of expectation due to lack of improved efficacy and higher-than-expected toxicities compared to R-CHOP. Bevacizumab is currently being evaluated in combination with pentostatin, cyclophosphamide and rituximab in patients with CLL in US.

Other anti-VEGF strategies that have been studied in lymphoma include VEGF-antisense and VEGF-Trap (aflibercept; Regeneron Pharmaceuticals). Levine reported a Phase I study of antisense oligonucleotide against VEGF-A in a small cohort of patients with malignancies, and observed a partial response in 1 patient with cutaneous T-cell lymphoma [108]. The VEGF-Trap molecule intercepts VEGF-A with the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human IgG [109]. VEGF-Trap has been evaluated either as a single agent or in combination with R-CHOP for NHL in phase I studies. No objective response was reported for lymphoma patients with the single agent [110], while the report on the combination therapy is still pending.

Receptor Tyrosine Kinase Inhibitors

Given the complexity of angiogenic pathways in tumor angiogenesis, it is assumed that biologic agents targeting

2Stopeck, A. T.; Unger, J. M.; Rimsza, L. M.; Farnsworth, B.; Leblanc, M.; Iannone,

M.; Fisher, R. I.; Miller, T. P. Phase II trial of standard dose cyclophosphamide,

doxorubicin, vincristine, prednisone (CHOP) and Rituximab (R-CHOP) plus

Bevacizumab for advanced stage diffuse large B-cell (DLBCL) NHL: Southwest

Oncology Group Study S0515. ASH Annual Meeting Abstracts, 2010, 116 (21), 591.

multiple signaling pathways operative in vascular stromal cells would achieve synergy compared to agents with single focus. Receptor tyrosine kinase inhibitors which at least partially target PDGF receptors have been shown to have anti-angiogenic functions by inhibition of vascular pericytes [111]. One such multi-target agent is sunitinib (SU11248), an orally bioavailable inhibitor that affects receptor tyrosine kinases including VEGF receptors 1, 2, 3 and PDGF receptors and . Its therapeutic effects are at least partially mediated via anti-angiogenesis by targeting both endothelial cells and pericytes, with activities demonstrated in gastrointestinal stromal tumors (GIST), renal cell carcinoma (RCC) and acute myeloid leukemia (AML), among other tumor types. Based on phase II and III studies in patients with metastatic RCC and GIST, sunitinib is FDA approved for metastatic RCC and imatinib-resistant GIST. Sunitinib has been studied in relapsed and refractory DLBCL and CLL/SLL, with study results awaited. Another compound of interest is dasatinib, which inhibits both c-Src tyrosine kinase and PDGFR . Dasatinib has been shown to hit the dual targets of tumor cells and vessels in multiple myeloma [112], and has activity in DLBCL [113]. Phase II studies with dasatinib in aggressive NHL is ongoing.

Immunomodulatory Drugs

Immunomodulatory drugs (iMiDs) are a series of synthetic compounds that have been developed based on the glutamate-derivative backbone of the prototype drug thalidomide. Thalidomide has wide-ranging functions including anti-inflammatory, immunomodulatory, anti-angiogenic and direct anti-cancer activities [114]. The anti-angiogenic function of thalidomide was thought to be mediated partially via inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis [115]. It has been shown that thalidomide can bind to cereblon (CRBN), a substrate receptor of E3 ubiquitin ligase complex containing


damaged DNA binding protein-1 which is important for limb outgrowth and expression of FGF 8 and 10 [116]. The second generation compounds lenalidomide and pomalidomide have enhanced immunological and anticancer properties with fewer side effects. Lenalidomide has been demonstrated to possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt phosphorylation in response to bFGF [117].

Thalidomide

Thalidomide has demonstrated clinical activity in both CLL and MCL. Single agent thalidomide demonstrated a limited and modest overall response rate of 12.5% when given at 200 mg daily escalating to a maximum 800 mg daily to patients with relapsed / refractory indolent NHL (SLL and FL) [118]. In combination with fludarabine, thalidomide was associated with significant therapeutic efficacy in CLL. In treatment-naïve patients, the combination of thalidomide (100-300 mg daily) and fludarabine (standard monthly dosing) achieved a 100% OR and 55% CR rate. The median time to disease progression was not reached at 15+ months [119]. In fludarabine-refractory patients, an OR rate of 31% was observed with the FR regimen

3. The combination of

thalidomide and rituximab (anti-CD20) was studied in a small phase II trial for patients with relapsed / refractory MCL [120]. Thirteen of 16 evaluable subjects demonstrated objective responses (5 CR, 8 PR, OR of 81% and CR of 31%), with median time to progression (TTP) at 20 months. The main toxicities of thalidomide include fatigue, somnolence, neuropathy and thromboembolic events, in addition to teratogenicity.

Lenalidomide

Lenalidomide has demonstrated significant clinical activity either as a single agent or in combination with rituximab against a variety of lymphoma subtypes, including both aggressive and indolent NHLs. Single agent lenalidomide given at 25 mg orally daily on days 1-21 every 28 days is effective in relapsed aggressive B-cell NHL [121-122] (35% ORR and 12% CR), indolent NHL (23% ORR and 7% CR/CRu) [123], MCL (ORR 53% and CR 20%) [124], and T-cell NHL (30% ORR) [125]. The combination of rituximab (375 mg/m

2 given weekly during cycle 1) and

lenalidomide (20 mg daily on days 1-21 every 28-day cycle) can be safely tolerated in relapsed MCL with significant activity (ORR 53% and CR 31%; median PFS 14 months; duration of response 18 months)

4. In upfront setting,

lenalidomide given at 20 mg daily on days 1-21 every 28 days plus rituximab given at 375 mg/m

2 on day 1 of each

cycle up to 6 cycles has been studied in patients with previous untreated indolent B-cell NHLs. Analysis of the first 30 study subjects demonstrated remarkable activity with

3Furman, R. R.; Leonard, J. P.; Allen, S. L.; Coleman, M.; Rosenthal, T.; Gabrilove, J.

L. Thalidomide alone or in combination with fludarabine are effective treatments for

patients with fludarabine-relapsed and refractory CLL. J. Clin. Oncol., 2005 ASCO

Annual Meeting Proceedings , 2005, 23 (supplement), abstract 6640. 4Wang, L.; Fayad, L.; Hagemeister, F. B.; Neelapu, S.; Samaniego, F.; Mclaughlin, P.;

Samuels, B.; Yi, Q.; Pro, B.; Fanale, M.; Shah, J.; Younes, A.; Bell, N.; Knight, R.;

Zeldis, J. B.; Cabanillas, F.; Kwak, L.; Romaguera, J. A phase I/II study of

lenalidomide in combination with rituximab in relapsed/refractory mantle cell

lymphoma. ASH Annual Meeting Abstracts, 2009, 114, 2719.

ORR of 86% and CR of 79%5. Lenalidomide has also been

studied in relapsed / refractory CLL. When administered orally at 25 mg on days 1 through 21 of a 28-day cycle to 45 patients with relapsed disease (51% refractory to fludarabine), lenalidomide achieved an overall response rate of 47% with 9% CR rate [126]. Ferrajoli and colleagues has reported the clinical outcome on lenalidomide given as a continuous low-dose treatment of 10 mg daily with dose escalation up to 25 mg daily as tolerated in 44 CLL patients [127]. The overall response rate was 31%, and CR rate was 7%. Over time, a statistically significant decline in plasma basic FGF, but not VEGF, was observed in responders compared to nonresponders. Treatment-related toxicities with lenalidomide were generally mild and moderate. Fatigue, rash and thrombosis, in addition to myelosupression with thrombocytopenia and neutropenia, were the most common adverse effects with the lenalidomide therapy.

Metronomic Therapy

In contrast to the conventional “maximum tolerated dose” (MTD) chemotherapy, metronomic chemotherapy administers low doses of medications on a frequent or continuous schedule without extended drug-free breaks [49, 128]. The main targets of metronomic therapy are the endothelial cells of the growing tumor vasculature [129]. In addition to targeting endothelium preferentially, metronomic therapy also effectively suppresses the surge of bone marrow-derived endothelial cell mobilization following conventional MTD therapy [102], thereby reducing rebound tumor angiogenesis.

Metronomic therapy has demonstrated efficacy in relapsed diseases. Buckstein and colleagues reported the clinical efficacy of oral combination celecoxib and low-dose cyclophosphamide in relapsed aggressive non-Hodgkin’s lymphoma [130]. In 35 heavily pretreated DLBCL patients, the overall best response rate was 37%, with 22% achieving stable disease. These observed clinical responses appeared to correlate with declining levels of circulating endothelial cells (CD45

-CD31

+CD146

+) and their precursors (CD45

-

CD31+CD146

+CD133

+) in responders, suggesting

angiogenesis inhibition as a potential mechanism of action [130]. Another metronomic lymphoma therapy which has been used by our group is the PEPC (C3) regimen. PEPC consists of low-dose prednisone (20 mg), etoposide (50 mg), procarbazine (50 mg) and cyclophosphamide (50 mg) administered orally with dosing frequency titrated to hematologic parameters (i.e. ANC above 1000). This regimen is well tolerated, and is associated with significant clinical activity in recurrent NHLs [131-132]. We have combined PEPC with two biologic agents that are active against MCL, namely rituximab and thalidomide [120], to comprise the RT-PEPC regimen in order to further improve the therapeutic index of metronomic therapy for relapsed / refractory MCL [73]. Interim analysis showed overall response rate was 73% with CR rate of 32%, and median PFS of 10 months. Correlative studies demonstrated

5Fowler, N. H.; Mclaughlin, P.; Hagemeister, F. B.; Kwak, L. W.; Fanale, M. A.;

Neelapu, S. S.; Fayad, L.; Orlowski, R. Z.; Wang, M.; Samaniego, F. Complete

response rates with lenalidomide plus rituximab for untreated indolent B-cell non-

Hodgkin's lymphoma. J. Clin. Oncol., 2010 ASCO Annual Meeting Proceedings, 2010,

28 (15s), abstract 8036.


autocrine expression of VEGFA and VEGFR1 by the tumor cells and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF and circulating endothelial cells trended down with treatment, consistent with response to antiangiogenic treatment.

Other Novel Biologics with Antiangiogenic Properties

Some biologic agents with direct cytotoxicities on tumor cells have shown antiangiogenic activities. They include the mTOR inhibitors, HDAC inhibitors, and proteasome inhibitors.

mTOR Inhibitors

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase downstream of PI3-kinase / AKT pathway [133]. mTOR-mediated phosphorylation activates two downstream targets, namely p70S6 kinase (p70S6K) and 4E-binding protein 1 (4E-BP1), which are essential in the regulation of cell growth, proliferation and survival [134]. Selective mTOR inhibitors have shown anti-angiogenic activities by inhibiting HIF-1 -mediated VEGF production downstream of the PI3-kinase/AKT/mTOR pathway, as well as direct inhibitory effect on endothelial cell proliferation [135-136].

mTOR inhibitor temsirolimus (CCI-779) has been studied in patients with relapsed mantle cell lymphoma. Temsirolimus was given at 250 mg intravenously every week as a single agent. A 38% response rate was observed in 34 evaluable patients, with a median time to progression (TTP) of 6.5 months. Thrombocytopenia was dose-limiting, but of short duration [137]. A randomized, open-label phase III study compared the antitumor activity of temsirolimus with an investigator’s choice of therapy in patients with relapsed MCL. Patients received treatment with temsirolimus had significant improvement in PFS (4.8 months vs. 1.9 months, p=0.0009) and objective response rate (22% vs. 2%, p=0.0019), compared with investigator’s choice [138]. The most common grade 3 AEs were cytopenias. Single agent temsirolimus has also shown significant activity in both diffuse large B-cell lymphoma (ORR of 28.1% and CR of 12.5%) and follicular lymphoma (ORR of 53.8% and CR of 25.6%), with durability of responses longer for patients with follicular lymphoma compared to DLBCL (median PFS of 12.7 months vs. 2.6 months) [139]. An oral derivative of rapamycin, everolimus (RAD001, Novartis), has shown clinical efficacy in mantle cell lymphoma, DLBCL, follicular lymphoma, CLL, and Waldenstrom macroglobulinemia [140-142].

HDAC Inhibitors

Histone deacetylases (HDAC) regulate chromatin remodeling and epigenetic modification of gene expression by deacetylation of histones. HDACs are grouped in four classes based on the structures of their accessory domains. Inhibition of HDAC activity causes an accumulation of acetylated proteins including histones and non-histone substrates, which leads to selective gene transcription alteration [143]. Histone deacetylase inhibitors (HDACi) represent an emerging class of therapeutic agents that induce tumor cell cytostasis, differentiation, and apoptosis, in part by angiogenesis inhibition. HDACi has been shown to

induce VHL-dependent HIF-1 degradation by acetylation at Lys532 [144]. Further, class II HDACs including HDAC4 and HDAC6 are physically associated with HIF-1 , and their selective inhibition by HDACi can induce HIF-1

acetylation and polyubiquitination in a VHL-independent mechanism [145]. HDACi can also alter VEGF signaling by inhibiting VEGF receptors and neuropilin-1 expression in endothelial cells [146].

To date, clinical studies with pan-HDAC inhibitors vorinostat (suberoylanilide hydroxamic acid, SAHA) and panobinostat (LBH589), as well as selective class I HDAC inhibitors romidepsin and MGCD0103, have been reported in NHL. Vorinostat, given orally at 400 mg daily, has demonstrated activity (ORR 24% - 29.2%) in heavily pretreated patients with cutaneous T-cell lymphoma (CTCL), which led to its approval by the U.S. Food and Drug Administration in 2006 for the treatment of progressive and recurrent CTCL [147-149]. Duvic and colleagues reported that successful therapy with vorinostat was associated with a reduced CD31

+ dermal microvessel density, and an increase

of the antiangiogenic protein thrombospondin-1 (TSP-1) following treatment [149]. Limited activity was noted for vorinostat in relapsed DLBCL [150]. Romidepsin (depsipeptide or FK228) is the second HDACi that has received the U.S. FDA approval in 2009 for patients with CTCL who have received at least one prior systemic therapy. Treatment with single agent romidepsin, administered as IV infusion at 14 mg/m

2 on days 1, 8, 15 every 28 days, led to a

median duration of response of 13.7-15 months and an overall response rate of 34% [151-152]. Panobinostat has also been evaluated in progressive CTCL [153]. Microarray analysis of skin biopsies showed distinct gene expression response profiles over time following panobinostat treatment, including consistent downregulation of proangiogenic genes guanylate cyclase 1A3 (GUCY1A3) and angiopoietin-1 (ANGPT1). MGCD0103 has shown activity in both DLBCL and FL

6. An interim analysis of 50

patients (33 DLBCL and 17 FL) showed 1 CR, 3 PRs (RR 23.5%) and 5 SDs in the evaluable 17 DLBCL patients, and 1 PR in the evaluable 10 FL patients. Additional HDAC inhibitors currently in clinical trials for lymphoma include belinostat (PXD101) and entinostat (SNDX-275). In general, HDACs can be safely administered with class-related common toxicities including transient cytopenia, nausea, diarrhea, fatigue, dehydration and QTc prolongation, which appear to be schedule, route, and dose dependent.

Proteasome Inhibitors

Inhibition of the ubiquitin-proteasome pathway in tumor cells hinders tumor growth by inducing cell cycle arrest, apoptosis and inhibiting tumor metastasis and angiogenesis. Bortezomib (PS341, Velcade

TM), a dipeptidyl boronic acid

derivative, selectively inhibits the 26S proteasome which is essential in the degradation of intracellular proteins including p53, nuclear factor kappa B (NF- B), bcl-2, and cyclin-dependent kinase (cdk) inhibitors such as p21 and p27

6Crump, M.; Andreadis, D.; Assouline, S.; Rizzieri, D.; Wedgwood, A.; Mclaughlin,

P.; Laille, E.; Li, Z.; Martell, R. E.; Younes, A. Treatment of relapsed or refractory

non-hodgkin lymphoma with the oral isotype-selective histone deacetylase inhibitor

MGCD0103: Interim results from a phase II study. J. Clin. Oncol., 2008 ASCO Annual

Meeting Proceedings, 2008, 26, Abstract 8528.


[154]. Bortezomib was shown to mediate anti-angiogenesis in myeloma patients via dose-dependent inhibition of VEGF and IL-6 secretion by endothelial cells [155]. Bortezomib has direct inhibitory effects on HIF-1 activation by reinforcing the factor inhibiting HIF-1 (FIH)-mediated inhibition of p300 coactivator recruitment [156]. Induction of HIF-1 (which was common in tumors under hypoxia) was shown to render endothelial cells particularly sensitive to the proapoptotic and anti-angiogenic effects of bortezomib [157], suggesting that bortezomib can selectively target tumor-associated vessels.

In non–Hodgkin’s lymphoma, several phase II studies [158-161] confirmed activity of single agent bortezomib in follicular, mantle cell, and marginal zone lymphoma. A multicenter pivotal trial determined that the overall response rate in relapsed MCL was 33%, including 8% complete remission (CR) /unconfirmed CR, with a median duration of response of 9.2 months and time to progression of 6.2 months [160], leading to FDA approval of bortezomib for this indication. The most common grade 3 AEs were peripheral neuropathy, fatigue, and thrombocytopenia. Bortezomib also has activity in other B-cell processes, including Waldenstrom’s macroglobulinemia and amyloidosis [162]. Currently multiple trials are ongoing to further exam its efficacy in combination with other active regimens in NHL.

CONCLUSION

Anti-angiogenic strategies are being actively explored in lymphoma. Single agent bevacizumab has limited activity in aggressive NHLs, while the combination of bevacizumab and the standard chemoimmunotherapy R-CHOP appear to have increased cardiovascular risks without improved efficacy compared to R-CHOP alone in patients with DLBCL. Targeting multiple components within the tumor microenvironment, immunomodulatory drugs such as thalidomide and lenalidomide have demonstrated clinical activity against a wide variety of NHL including DLBCL, CLL and MCL, either as single agent or in combination with rituximab or chemotherapy. Metronomic low dose chemotherapy appears to have broad clinical applicability in lymphoma, particularly in relapsed and refractory settings. Novel biological agents, targeting receptor tyrosine kinases (RTK) including multiple VEGF receptors and PDGF receptors, and distinct downstream targets along the angiogenic signaling pathways which regulate HIF-1 and VEGF expression, are in various stages of clinical development and investigation in human lymphoma patients.

Based on these preliminary clinical data in lymphoma as well as the therapeutic experiences with solid tumor malignancies, there are several important lessons to consider for further development of effective antiangiogenic therapy. First, molecular regulation of tumor angiogenesis is complex and incompletely understood in the context of various lymphoma subtypes. Therefore, translational research is much needed to establish angiogenesis-specific prognostic markers, and to validate subtype-specific therapeutic targets. Second, biologics aiming at stromal targets implicated in angiogenesis, such as anti-VEGF bevacizumab, may not have direct cytotoxic effects on tumor cells. When applied

alone, these compounds often exhibit limited control of tumor growth. To improve the treatment efficacy with anti-vascular agents, combination approach should be encouraged to add other drugs that target more directly the malignant tumor cells. Third, serious side effects such as hypertension, heart failure, stroke and thrombosis can occur in susceptible hosts with antiangiogenic compounds due to therapeutic modulation on normal vasculature. Clinical study designs need to balance desired treatment efficacy with potential toxicities. Lastly, prospective correlative studies should be included with clinical trials whenever possible to validate mechanisms of action and develop clinically useful prognostic biomarkers. This information will provide much-needed insights for the rational design of future effective anti-angiogenic therapy and schedules that are tailored to appropriate clinical settings.

FINANCIAL DISCLOSURE

J.R. has received research support from Genentech and Celgene.

RESEARCH GRANTS

Supported in part by an ASCO Career Development Award and NIH grant K08HL091517 to J.R.

DISCLOSURE

The content of this article have been taken and modified from “Ann. Oncol. 2009 Mar; 20(3): 413-24. Epub 2008 Dec 16”.

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Received: August 19, 2011 Revised: September 18, 2011 Accepted: September 18, 2011

PMID: 21933106

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