VEGF Targeted Therapy in Acute Myeloid Leukemia

Critical Reviews in Oncology/Hematology 80 (2011) 241–256

VEGF targeted therapy in acute myeloid leukemia

a a b c,∗

Antonio Rodriguez-Ariza , Chary Lopez-Pedrera , Enrique Aranda , Nuria Barbarroja

Unidad de Investigación, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba, IMIBIC, Córdoba, Spain

Servicio de Oncología, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba, IMIBIC, Córdoba, Spain

Laboratorio de Investigaciones Biomédicas, Fundación IMABIS, Hospital Universitario Virgen de la Victoria, Málaga, Spain

Accepted 28 September 2010

Contents

1. Introduction ...... 242

2. VEGF-targeted approaches for AML ...... 243

2.1. Neutralizing antibodies ...... 243

2.2. Receptor tyrosine kinase inhibitors...... 245

2.2.1. Sunitinib (SU11248 or SU01248) ...... 245

2.2.2. Semaxinib (SU5416) ...... 246

2.2.3. SU5614 ...... 246

2.2.4. Sorafenib (BAY43-9006) ...... 246

2.2.5. Lestaurtinib (CEP-701) ...... 247

2.2.6. Midostaurin (PKC412) ...... 247

2.2.7. Axitinib (AG-013736) ...... 247

2.2.8. Cediranib (AZD2171) ...... 248

2.2.9. Vatalanib (PTK787/ZK 222584) ...... 248

2.2.10. Vandetanib (ZD6474) ...... 248

2.2.11. AEE788 ...... 249

2.3. Statins ...... 249

2.4. Arsenic trioxide...... 250

3. Conclusions ...... 251

Conﬂict of interest ...... 251

Reviewers ...... 251

Acknowledgement ...... 252

References ...... 252

Biographies...... 255

Abstract

The cooperation of two classes of mutations in hematopoietic cells is hypothesized in a multistep pathogenesis model of acute

myeloid leukemia (AML). Class I mutations confer a proliferative and/or survival advantage, whereas Class II mutations block

hematopoietic differentiation and impair apoptosis in AML cells. In addition to these two classes of mutations, a relevant role for

angiogenesis in the pathophysiology of AML has been recently proposed. The recognition that the vascular endothelial growth fac-

tor (VEGF) pathway is a key regulator of angiogenesis has led to the development of several VEGF-targeted approaches. These

include neutralizing antibodies, VEGF traps or selective tyrosine kinase inhibitors for VEGFRs. Other drugs that indirectly affect VEGF

∗

Corresponding author. Tel.: +34 951 03 26 48.

E-mail address: [email protected] (N. Barbarroja).

242 A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256

pathway, such as statins or arsenic trioxide, also have been shown to possess antiangiogenic activity in leukemias. The beneﬁts of these VEGF

targeted agents and their current stage of development as novel anti-antiangiogenic therapies in AML are discussed in this review.

Keywords: AML; VEGF; Tyrosine kinase inhibitors; Arsenic trioxide; Statins

1. Introduction tions are also referred to as FLT3 tyrosine kinase domain

mutations (FLT3/TKD). Although both types of mutation

Acute myeloid leukemia (AML) is a clonal disorder which lead to constitutive activation of the receptor, FLT3/ITDs

is the consequence of acquired somatic mutation that occurs and FLT3/TKDs promote different downstream effectors and

in a hematopoietic progenitor. The molecular pathogeny of different biological responses [6,7]. These mutations cause

AML is to some extent dependent on the age of the population FLT3/WT and FLT3/ITD–TKD to behave in different ways.

under consideration. In children and younger adults, balanced In these sense, it has been shown that several receptor tyro-

chromosomal translocations are relatively common, while in sine kinase inhibitors have different activity against wild

older patients AML is characterized by a more common pic- type and mutated FLT3. These inhibitors usually bind to

ture of chromosomal losses and gains, often in the context FLT3/ITD with increased afﬁnity, probably due to differences

of a complex karyotype. Evidence to date suggests that kary- in conformation between FLT3/WT and FLT3/ITD receptors;

otype identiﬁes biologically distinct subsets of disease and is accessibility to drug may be inﬂuenced by differences in cel-

highly predictive of response to therapy and overall survival lular localization; or levels of ligand necessary to stimulate

[1]. phosphorylation of FLT3/WT in vitro may be higher than

The generation of chimeric fusion proteins, through physiologic levels.

chromosomal translocations, which lead to a block in dif- FLT3 mediates proliferation and anti-apoptotic

ferentiation and contribute to the biological characteristics of effects through several signalling pathways, including

different subsets of leukemia, is generally believed to be a pri- the Ras/MAPK, JAK/STAT and PI3K/Akt pathways [6,8,9].

mary event in the pathogenesis of AML. Nevertheless, over Nevertheless, studies in our lab have demonstrated that the

the last few years it has become apparent that mutations in inhibition of mutated FLT3 receptor does not prevent the

genes encoding components of the signal transduction path- constitutive activation of ERK, Akt or STAT in some primary

ways are frequent in AML; these include activating mutations AML blasts that hold the FLT3 mutation, suggesting that

of FLT3, RAS, KIT, and SHP2. Therefore a multistep patho- additional cytogenetic alterations, such as the Ras or JAK

genesis model of AML has been hypothesized [2] where mutations, which activate ERK and Akt, might be necessary

AML is the consequence of a cooperation between two broad to induce the abnormal signal transduction found in these

classes of mutations: Class I mutations, that confer a pro- cells [10].

liferative and/or survival advantage to hematopoietic cells In addition to these two classes of mutations, it has been

by constitutively activating tyrosine kinases or their down- proposed the relevant role of angiogenesis in the patho-

stream effectors, and Class II mutations that primarily impair physiology of AML. A balance between pro-angiogenic and

hematopoietic differentiation and may provide a selective antiangiogenic growth factors and cytokines tightly controls

advantage for these cells as well by impairing subsequent angiogenesis [11,13]. Although the role of angiogenesis in

apoptosis. Regardless of the timing or order of acquisition the growth of solid tumors has been studied extensively,

of mutations, individuals with both Class I and Class II investigation of the importance of this process in hematologic

mutations have a clinical phenotype of AML characterized malignancies has been recognized only recently. Earliest

by a proliferative and/or survival advantage to cells and by studies revealed that bone marrow inﬁltrated by AML blasts

impaired hematopoietic differentiation. exhibits an increased microvessel density compared to nor-

Among the Class I mutations, activating mutations in mal bone marrow [12,14], and microvessel density decreased

hematopoietic receptor tyrosine kinases (RTKs) are frequent in response to induction therapy [14].

events in AML and are associated with poor prognosis [3–5]. One of the most speciﬁc and critical regulators of

Mutation of the FLT3 gene encoding Fms-like tyrosine kinase angiogenesis is vascular endothelial growth factor (VEGF),

3 is one of the most common genetic lesions identiﬁed in which regulates endothelial proliferation, permeability, and

AML thus far, being detected in almost one third of cases. survival. In mammals, VEGF family consists of ﬁve glyco-

The majority are length mutations (internal tandem duplica- proteins referred to as VEGFA, VEGFB, VEGFC, VEGFD

tions, FLT3/ITDs) involving the juxtamembrane region of the (also known as FIGF) and placenta growth factor (PlGF,

receptor, which contains the inhibitory signal for the tyrosine also known as PGF) [15]. The best characterized of the

kinase. Alternative and less frequent mutations (approxi- VEGF family members is VEGFA (commonly referred to

mately 4–7% of AML cases) are localized in the activation as VEGF), which is expressed as various isoforms derived

loop of FLT3 (FLT3/ALMs), which normally blocks access from alternative splicing that leads to mature 121-, 165-,

of ATP and substrate to the kinase domain. These muta- 189- and 206-amino-acid proteins. VEGF165 is the predom-

A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256 243

inant isoform and is commonly overexpressed in a variety density, VEGF and VEGFR1 overexpression have demon-

of human tumors [16]. Three structurally similar type III strated correlation with lower remission rate and reduced

receptor tyrosine kinases, designated VEGFR1 (also known overall survival in AML patients [14,26].

as Flt-1), VEGFR2 (also known as KDR) and VEGFR3 (also Recognition of the VEGF pathway as a key regulator of

known as FLT4) are activated upon binding of VEGF lig- angiogenesis in haematologic malignancies has led to the

ands. Leukemia cells commonly express one or both of the development of several VEGF-targeted approaches. These

major VEGF receptor tyrosine kinases, the c-fms-like tyro- include neutralizing antibodies to VEGF or VEGF receptors,

sine kinase (Flt-1) and the kinase domain receptor (KDR) soluble VEGF receptors or tyrosine kinase inhibitors (TKIs)

and can produce and secrete VEGF [17]. with selectivity for VEGFR receptors (Fig. 1). Other drugs

As for other receptor tyrosine kinases, VEGF bind- that indirectly affect VEGF pathway, such as statins or arsenic

ing to the receptor leads to receptor homodimerization or trioxide, have also been shown to possess antiangiogenic

heterodimerization and subsequent autophosphorylation on activity in AML (Fig. 2). The beneﬁts of these VEGF tar-

certain tyrosine residues, which in turn triggers intracellu- geted agents and their current stage of development as novel

lar signaling cascade mediated by several effectors, which anti-antiangiogenic therapies in AML will be detailed below.

are able to recognize and dock at phosphorylated tyro-

sine residues of the activated receptors. These interactions 2.1. Neutralizing antibodies

are mediated by Src homology 2 (SH2), phosphotyrosine-

binding, and other domains of the signaling proteins [18]. Bevacizumab (rhuMAb VEGF, Avastin, Genentech, Inc)

There is now much evidence that VEGFR2 is the major is a recombinant humanized monoclonal antibody (MAb)

mediator of VEGF-driven responses in endothelial cells and that targets VEGF-A isoform and blocks its binding to the

it is considered to be a crucial signal transducer in both VEGF receptors [27]. Bevacizumab has been approved as

physiologic and pathologic angiogenesis. VEGFR2 signaling a treatment for several solid tumors, including metastatic

pathways are relatively well understood. In human VEGFR2 colorectal cancer, nonsquamous cell lung cancer, metastatic

the major autophosphorylation site following VEGF bind- breast cancer, metastatic renal cell cancer, prostate can-

ing is Y1175, that serves as a docking site for phospholipase cer, and glioblastoma [28]. A recent study performed

C-gamma, which indirectly mediates activation of the mito- in nine patients with relapsed or refractory AML not

gen activated protein kinase pathway and thus regulates cell ﬁt to intensive chemotherapy showed that bevacizumab

proliferation. In addition, Y1175 is a binding site for other treatment was well tolerated with a favourable safety pro-

adaptor molecule, such as Src homology 2 (SH2) domain- ﬁle. Monotherapy with bevacizumab signiﬁcantly caused

containing protein containing adaptor protein B (Shb) [19]. decrease of VEGF expression without signiﬁcant change

Interaction between Shb and phosphorylated Y1175 of in VEGFR2 expression and phosphorylation in bone mar-

VEGFR2 is required for VEGF-dependent activation of phos- row of these AML patients. However, none of the patients

phatidylinositol 3-kinase/Akt antiapoptotic pathway [20]. A had a clinical response [29]. Nevertheless, the combination

second major autophosphorylation site in human VEGFR2 of bevacizumab and chemotherapeutic agents, such as 1-b-

is Y1214, which is involved in activation of Cdc42 and p38 d-arabinofuronosylcytosine (ara-C) and mitoxantrone in a

mitogen-activated protein kinase [21]. phase II clinical trial in AML patients resulted in enhanced

Autocrine and paracrine growth stimulation with VEGF antitumor activity compared to either agent alone. The overall

results in a mitogenic response within hematologic malig- response rate was 48%, including complete responses (33%)

nancies and speciﬁcally promotes self-renewal of leukemia and partial responses (14.5%). Serum VEGF levels decreased

progenitors [17,22,23]. The pivotal role for autocrine VEGF within 2 h after bevacizumab treatment, and reduced the bone

loops in hematological malignancies is conﬁrmed by the co- marrow microvessel density over the course of 7 days. These

expression of both VEGF and VEGF receptors in leukemia, results support the use of bevacizumab in combined therapy

lymphoma and multiple myeloma coupled with its direct in AML patients that are resistant to traditional treatment

effects on tumor cell survival migration, and proliferation approaches [30].

[24]. Moreover, it has been shown that there is autocrine acti- Aﬂibercept (VEGF Trap) is a recombinant protein con-

vation in the expression of VEGF and other proangiogenic sisting of domain 2 from VEGFR1 fused to domain 3 from

molecules such as tissue factor in AML blasts [25]. VEGFR2, attached to the hinge region of the Fc(a) domain

of human immunoglobulin (Ig) G1. VEGF Trap is a circulat-

ing antagonist that prevents VEGF receptor binding which

2. VEGF-targeted approaches for AML binds VEGF-A more tightly than monoclonal antibodies.

VEGF Trap has a relatively long half-life, of approximately

Prognostic variables in myeloid malignancies are critical two weeks. Phase I clinical trials have evaluated the safety,

tools for estimating survival expectation and stratify- pharmacokinetics, and pharmacodynamics of VEGF Trap in

ing patients according to optimal treatment approaches. advanced solid tumors. VEGF blockade and partial responses

Although the prognostic signiﬁcance of angiogenic mark- were observed [31]. Currently, a multi-center phase II study

ers remains largely conﬂicting, measurements of microvessel of VEGF Trap as a single agent in AML is undertaken.

244 A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256

Fig. 1. Chemical structures of VEGFRs inhibitors.

Monoclonal antibodies with high afﬁnity for human VEGF-induced migration of human leukemia cells in vitro,

VEGFR2 have also been generated, such as IMC-1121 which and when administered in vivo, signiﬁcantly prolonged sur-

blocked VEGF/KDR interaction with an IC50 of approx- vival of mice inoculated with human leukemia cells [32]. The

imately 1 nM. This anti-KDR antibody strongly inhibited effect of IMC-1121 is now being evaluated in a phase II study

Fig. 2. Action mechanisms of angiogenic inhibitors in AML cell.

A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256 245

Table 1

Anti-angiogenic agents.

Agent Target Phase of development in solid Phase of Ref.

tumors development in

AML

Bevacizumab VEGF ligand Approved for colorectal, Phase II Mukherji et al. [28]; Karp et al.

nonsquamous cell lung, breast, [30]

renal cell, prostate cancers, and

glioblastoma, phase II/phase III

for other cancers

Aﬂibercept (VEGF Trap) VEGF ligand Phase I for advanced solid tumors Phase II Lockhart et al. [31]

IMC-1121 VEGF receptor, Phase II for advanced solid In vitro studies Zhu et al. [32]

extracellular domain tumors

Sunitinib (SU11248) VEGFR1, 2, 3, PDGFR, Approved for kidney cancer and Phase I Vroling et al. [34]; Heinrich et al.

KIT, FLT3, CSF-1R, RET GIST, phase II or III for other [35]; Fiedler et al. [37]

cancers

Semaxinib (SU5416) VEGFR1, 2, KIT, FLT3 Phase I or II Phase II Fiedler et al. [45]; O’Farrell et al.

[46]; Salzberg et al. [47]

SU5614 VEGFR1, 2, KIT, FLT3 In vitro studies Aleskog et al. [51]; Arseni et al.

[52]; von Bubnoff et al. [53]

Sorafenib (BAY43-9006) VEGFR-2, -3, PDGFR, Approved for kidney and liver Phase I Llovet et al. [57]; Delmonte et al.

Raf, KIT cancer, phase II or III for other [58]; Zhang et al. [59]; Safaian et

cancers al. [60]; Metzelde et al. [61]

Lestaurtinib (CEP701) VEGFR2, FLT3, KIT, Phase I Phase III Chan et al. [64]; Knapper et al.

FMS, PDGF-␤ [65,66]

Midostaurin (PKC412) PKC, VEGFR2, PDGFR, Phase II Phase III Millward et al. [69]; Stone et al.

KIT, FLT3 [70]

Axitinib (AG-013736) VEGFR1, 2, 3,PDGFR, Phases II and III Phase II Kelly and Rixe [77]; Giles et al.

KIT [78]; Giles et al. [79]

Cediranib (AZD2171) VEGFR1, 2, 3, Phase II/phase III Phase I Lindsay et al. [84]; Fiedler et al.

PDGFR-␤, KIT [85]

Vatalanib (PTK787/ZK VEGFR1, 2, 3, PDGFR, Phase II or III Phase I Roboz et al. [95]; Joensuu et al.

222584) KIT, FMS [91]; George et al. [94]; Sharma

et al. [92]

Vandetanib VEGFR2, EGFR, RET, Phase II or III In vitro studies Morabito et al. [100]; Nishioka et

KIT, FLT3 al. [40]; Jia et al. [101]

AEE788 VEGFR1, 2, EGFR Phase I In vitro studies Xiong et al. [105]; Baselga et al.

[106]; Martinelli et al. [107];

Reardon et al. [108]

in advanced solid tumors, but has not yet been tested for the has been approved for the treatment of advanced kidney can-

treatment of AML. cer [34] and tumors that are resistant to imatinib, such as

gastrointestinal tumors [35].

In vitro AML studies demonstrated that sunitinib

2.2. Receptor tyrosine kinase inhibitors

signiﬁcantly decreased VEGF production and potently inhib-

ited the FLT3/ITD phosphorylation [36]. These authors

In the last few years many VEGF receptor tyrosine kinase

reported that signaling downstream of both FLT3/WT and

inhibitors have been developed and tested in solid tumors.

FLT3/ITD resulted in VEGF production. They claimed

Currently, most of them are being evaluated in open clinical

the novel ﬁnding that FLT3 signaling leads to secre-

trials for AML treatments (Table 1).

tion of VEGF in vitro, most notably in FLT3/ITD

cell lines, since FLT3 ligand was additioned to RS4:11 and

2.2.1. Sunitinib (SU11248 or SU01248) OC1-AML5 cell lines (which expressed low levels of VEGF)

Sunitinib is an orally active inhibitor of at least eight RTKs and they observed that VEGF production was increased by

including all VEGFRs (VEGFR1, VEGFR2 and VEGFR3), 3- to 4-fold in each cell line. In their experiments, sunitinib

␣

platelet-derived growth factor receptors (PDGFR and inhibited the VEGF expression levels induced by the addition

␤

PDGFR ), cKIT, FLT3/WT, and colony-stimulating factor- of FLT3 ligand. In addition, sunitinib inhibited VEGF pro-

1 receptor (CSF-1R), and is effective at low concentrations duction in MV4:11 cell line (FLT3/ITD) in a dose-dependent

(nM) [33]. Sunitinib inhibits angiogenesis by blocking sig- manner with an IC50 of approximately 10 nM. Thus, the

␤

naling through VEGFR1, VEGFR2, and PDGFR . Renal cell authors suggested that sunitinib inhibits VEGF production

cancers that have metastasized or spread from the primary due to inhibition of FLT3 signaling.

tumor, exhibit extensive vascularity, and sunitinib shows efﬁ- Sunitinib was investigated against AML in a phase I clini-

cacy in the treatment of these tumors. Currently, sunitinib cal trials. Overall, a single dose of sunitinib was well tolerated

246 A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256

at doses from 50 mg to 300 mg. At molecular levels, down- 2.2.3. SU5614

stream effects of sunitinib in AML patients, such as inhibition Compared to SU5416, the molecular structure of SU5614

of STAT5 and ERK kinases, probably are due to the inhi- was modiﬁed by a chloride substitution at the C-5 position

bition of receptors such as VEGFR. Moreover, 100% of of indolin-2-one. This compound was designed as a selective

FLT3/ITD patients had partial responses compared with 20% inhibitor of VEGFR1 and VEGFR2 activity at submicromo-

of FLT3/WT patients. However, the responses in both types lar levels [49]. In vitro studies showed that SU5416 was a

of patients were of short duration [37,38]. The effect of com- potent inhibitor of the VEGF-induced endothelial cell sprout-

bined treatment with sunitinib plus traditional antileukemic ing. In AML cells this inhibitor induced growth arrest and

agents (cytarabine or daunorubicin) on the proliferation and apoptosis; however there was no correlation between VEGFR

survival of AML cells were analyzed. Sunitinib was shown expression and sensitivity to the growth inhibitory activ-

to have additive inhibitory effects in AML FLT3/ITD cell ity of SU5614. The inhibitory effect was dependent on the

survival when combined with cytarabine or daunorubicin. In expression of the receptor kinase c-KIT [50]. However, this

contrast, the effects of these combinations were not different compound efﬁciently inhibited the VEGF-induced capillary

than those seen when each agent was administered separately sprouting of endothelial cells in a dose-dependent manner.

in AML FLT3/WT [39]. Furthermore, it has been shown These authors suggested that SU5614 had a dual mode of

recently that the blockade of MEK/ERK signaling potenti- action in the treatment of AML, inhibiting c-KIT in AML

ated the ability of sunitinib to inhibit the growth and to induce cells and VEGFR2 in endothelial cells. In this way, SU5614

apoptosis in AML cell lines [40]. So far, the overall data blocks two signalling pathways which are critical for the

seem suggest that sunitinib therapy could improve treatment molecular phenotype of AML.

results exclusively in AML patients harbouring FLT3/ITD Combinations of SU5614 with cytotoxic agents (etopo-

mutation. side and amsacrine) showed better effect compared with

the monotherapy [51]. Moreover, other study performed in

peripheral blood and bone marrow cells demonstrated the

2.2.2. Semaxinib (SU5416)

efﬁcacy of SU5416 at eliminating leukemic stem cells in

SU5416 is a potent inhibitor (IC 0.1 ␮M) of VEGFR1,

50 AML patients. However, the data also pointed to a consid-

VEGFR2 and cKIT phosphorylation [41]. Thereafter, it was

erable toxicity to normal hematopoietic stem cells, which

shown that also inhibited cellular phosphorylation of both

should be taken into account in the management of patients

wild-type FLT3 and FLT3/ITD mutants (IC , 0.1–0.25 ␮M)

50 with compromised normal hematopoiesis [52].

[42]. Semaxinib inhibits VEGF-dependent endothelial cell

proliferation in vitro and in animal models, due to the

inhibition of the phosphorylation of its VEGFR2 receptor. 2.2.4. Sorafenib (BAY43-9006)

Moreover,

it produces a dose-dependent inhibition of tumor BAY43-9006 or sorafenib, a novel bi-aryl urea, was ini-

growth

in a variety of xenograft models, including malignant tially developed as a speciﬁc inhibitor of C-Raf and B-Raf.

melanoma, glioma, ﬁbrosarcoma, and carcinomas of the lung, Subsequent studies revealed that this compound also inhibits

breast,

prostate and skin [43]. several other important tyrosine kinases involved in tumor

vitro studies in blasts from AML patients have shown a progression, including VEGFR2, VEGFR3, PDGF-␤, and c-

parallel downregulation of the expression of VEGF and key KIT [54]. The IC50 values for VEGFR2, VEGFR3, FLT3,

signal

transduction intermediates, such as STAT5 and Akt, c-KIT and PDGFR␤ were 90, 20, 32.6, 68 and 57 nmol/L,

after treatment with semaxinib [44]. These authors showed respectively.

that

semaxinib decreased VEGF levels in AML blast from The mechanism of action of sorafenib is being widely

72%

of patients analyzed. Moreover, patients with higher lev- studied. It initially inhibited tumor cell proliferation by tar-

els

of VEGF suffered a stronger inhibition and higher clinical geting the MAPK pathway at the level of Raf kinase in

response rate than patients that expressed low levels of VEGF. various tumor cell lines, including those harboring mutant

A multicenter phase II study with semaxinib was car-

Ras or B-Raf [55]. Recent works reported that sorafenib

ried

out in 43 patients with refractory AML using a dose of also induced marked mitochondrial damage manifested by

145

mg/m . The results showed that patients with AML blasts cytochrome c and apoptosis-inducing factor release into the

expressing high levels of VEGF mRNA had a signiﬁcantly

cytosol, caspase activation, and apoptosis in several tumor

higher

response rate and reduction of bone marrow microves- cells, including human leukemia cells [56]. It has been shown

sel density than patients with low VEGF expression [45]. that sorafenib inhibits tumor-cell proliferation and tumor

Semaxinib monotherapy was investigated in various multi- angiogenesis and increases the rate of apoptosis in a wide

center

phase II studies in refractory AML patients; however range of tumor models [55]. The inhibition of tumor growth

semaxinib

had modest clinical activity [46]. Overall median and stabilization of tumor was correlated with a decrease of

survival was 12 weeks with grade 3 or 4 leukemia-speciﬁc

tumor angiogenesis, which was due to inhibition of VEGF-

adverse

effects, probably due to the drug formulation [48], mediated endothelial cell. Currently, it is undergoing phase

which

is currently a major issue in the development of this II/III clinical evaluation in advanced solid tumors, including

drug.

hepatocellular carcinoma [57].

A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256 247

In addition to the inhibition of VEGFR2 and VEGFR3, cially blocking the VEGF-induced angiogenic process was

sorafenib also interacts with FLT3/ITD at an IC50 of 2 nM, comparable to that observed with a monoclonal antibody

whereas the IC50 for FLT3/WT cells was 3000 nM. A phase that inhibit the activity of VEGF or sequestered VEGF with

I trial to evaluate the safety and the efﬁcacy of two differ- excess amounts of soluble extracellular domain of VEGFR1

ent schedules of sorafenib in 20 AML patients was reported. in vivo. Thus, through the inhibition of VEGF, this compound

The authors concluded that this inhibitor was safe in AML caused inhibition of endothelial cell proliferation, migration

[58]. Thereafter, sorafenib was tested in other clinical study capillary formation and tumor vascularisation. Moreover,

on 16 patients with AML, and was found to be particu- midostaurin showed broad antiproliferative activity against

larly active in six of the seven FLT3/ITD positive patients. various tumor cell lines, including those that were resistant

However, treatment duration was short (21–70 days) and no to several other chemotherapeutic agents [68].

durable responses were reported [59]. Notably, a complete A phase II clinical trial was undertaken in advanced AML

molecular remission has recently been reported in a patient patients. Three-daily oral doses of 75 mg reduced peripheral

relapsing after stem cell transplantation (SCT) [60]. In addi- and bone marrow blasts counts in the majority of the patients.

tion, other authors have shown that sorafenib-monotherapy However, these beneﬁts were short-lived, lasting only 2–3

prior or post allo-SCT had remarkable clinical activity in months [70].

FLT3/ITD-positive AML [61]. All these recent studies sug- Some in vitro studies were carried out to compare the

gest that sorafenib deserves further evaluation in prospective efﬁcacy of midostaurin and lestaurtinib in AML cells. The

clinical trials. results showed that the cytotoxic effects of midostaurin was

more limited, probably due to the inhibition by lestaurtinib of

2.2.5. Lestaurtinib (CEP-701) other cellular targets upstream of STAT5 [65,71]. Neverthe-

Lestaurtinib is an orally bioavailable indolocabazole alka- less, phases I and II clinical trials of lestaurtinib and PKC412

loid compound that is synthetically derived from the bacterial monotherapy in similar patient AML groups have demon-

fermentation product K-252a. It is a potent FLT3 inhibitor strated very similar rates and degrees of clinical response

with an in vitro IC50 of 3 nM [62]. This inhibitor also dis- [63,70].

plays low nanomolar inhibition of VEGFR2 (IC50 = 65 nM). As the observed reductions in blast number produced by

However, it is not a potent inhibitor of other tyrosine midostaurin were of relatively short duration, it was thought

kinase receptors: IC50 greater than 500 nM against c- that the combination of midostaurin with other agents, such

KIT, FMS and PDGF-␤. Although lestaurtinib inhibits as a HDAC inhibitor, a HSP90 inhibitor, rapamycin with

VEGFR2, its cytotoxic effect was due to the inhibition chemotherapy could achieve a better response. All these stud-

of FLT3 phosphorylation, since lestaurtinib produced a ies showed a positive effect of the combined therapy with

phosphorylation-dependent reduction in cell growth and sur- midostaurin [65,72–74]. New diagnosed AML patients were

vival of AML cells that express FLT3 [62]. treated with midostaurin concurrently with induction ther-

Lestaurtinib was initially tested in phase II study in apy (daunorubicin and cytarabine). Complete remission was

patients with refractory o relapsed or poor-risk AML [63,65]. achieved in 71% patients [75]. Midostaurin is now being

The results were positive; the cytotoxic response required at investigated in a phase III trial in AML combined with

least an 80% inhibition of FLT3 autophosphorylation. The chemotherapy.

dose of lestaurtinib necessary to reach this threshold varied

between patients [65] and was likely to be higher in AML 2.2.7. Axitinib (AG-013736)

patients with FLT3/WT [66]. Axitinib is an orally available potent small molecule

In vitro, lestaurtinib showed a synergic effect with stan- inhibitor of VEGFR1 and VEGFR2 phosphorylation, with

dard chemotherapy, simultaneously or immediately given an IC50 of 1.2 and 0.25 nM, respectively. VEGFR3, cKIT,

␤

after chemotherapy [67]. AML patients in ﬁrst relapse show- PDGFR- and PDGFR-␣ were also inhibited by axitinib

ing activating mutations of FLT3 were randomized to receive to a signiﬁcant degree (IC50 values of 0.29, 1.7, 1.6 and

open-label chemotherapy alone or chemotherapy followed by 5 nM, respectively). However, it has little activity against

lestaurtinib. Half of these patients achieved complete remis- other type III receptors such as FLT3 (IC50 > 1000 nM)

sion [80]. Lestaurtinib is one of the most efﬁcient tyrosine [76]. In in vitro and in clinical studies, axitinib inhibited

kinase inhibitors in AML and have now reached phase III VEGF-mediated endothelial cell survival, tube formation,

clinical trials. and downstream signaling through endothelial nitric oxide

synthase, Akt and ERK pathways. It also produced consistent

2.2.6. Midostaurin (PKC412) and dose-dependent antitumor efﬁcacy that was associated

Midostaurin was identiﬁed as an inhibitor of PKC with blocking VEGFR2 phosphorylation, vascular perme-

and other molecular targets, including VEGFR2 (86 nM), ability, angiogenesis, and concomitant induction of tumor

VEGFR1 (900 nM), PDGFR␣, PDGF␤ (IC50 = 80 nM), c- cell apoptosis in solid tumors [76]. Axitinib is currently

KIT (IC50 = 500 nM), FLT3 (IC50 < 10 nM). Midostaurin in phases I–III development in a range of solid tumors. In

was an inhibitor of angiogenesis, though the inhibition of phase II studies, axitinib showed activity in a wide range of

VEGFR2 phosphorylation. The effects of midostaurin in spe- tumor types, including advanced renal cell carcinoma, thy-

248 A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256

roid cancer, malignant melanoma, pancreatic, breast, lung angiogenic strategies on the growth plate of growing children,

and colorectal carcinomas. Ongoing phase III studies in pan- a normal physiological role for the VEGF system [81]. On

creatic and metastatic renal cell carcinoma will ultimately the contrary, this inhibitor clearly showed a cytotoxic effect

deﬁne the therapeutic role of this targeted agent [77]. in an AML cell line, Kasumi-1 [86]. In this way, a phase I

A ﬁrst phase II study evaluated the effects of axitinib clinical study has been recently carried out in thirty-ﬁve adult

in eight elderly patients with poor prognosis AML. This patients with AML refractory to induction chemotherapy or

inhibitor was generally well tolerated and two patients had in relapse following ﬁrst or subsequent induction treatments,

stable disease of signiﬁcant duration [78]. Thereafter, the or elderly patients with de novo or secondary AML. Dose-

same authors conducted a phase II clinical trial in six poor and time-dependent reductions in VEGFR2 were observed

prognosis elderly AML patients to determine the overall after treatment with cediranib. Also, they found that there

response rate of axitinib. Moreover, pharmacokinetic analy- was a positive correlation between cediranib exposure and

ses and the effects of this inhibitor on bone marrow cells and the change in plasma VEGF levels. After cediranib treatment,

expression of angiogenic factors were evaluated. The results 19% of AML patients experienced an objective response and

showed that monotherapy with axitinib had minimal clini- bone marrow blasts were reduced in the majority of patients.

cal activity, probably due to lower VEGFR1 and VEGFR2 Taken together, cediranib monotherapy demonstrated a mod-

expression or the presence of other activating mutations in est clinical activity in AML patients [87].

this elderly population [79]. As the results were not satis-

factory, these data would not support the use of axitinib as 2.2.9. Vatalanib (PTK787/ZK 222584)

induction therapy in patients with AML. Vatalanib is an oral angiogenesis inhibitor targeting

VEGFRs tyrosine kinases, including VEGFR1, VEGFR2,

2.2.8. Cediranib (AZD2171) VEGFR3, PDGFR and c-KIT. It is slightly more potent

␮

Cediranib, also known as AZD2171, is a highly, potent against VEGFR2 (IC50 = 0.037 M) than against VEGFR1

␮

(subnanomolar IC50) and selective inhibitor of VEGF signal- (IC50 = 0.077 M). It also inhibits VEGFR3 and PDGFR

␮ ␮

ing, with activity versus all VEGFRs, and also has additional at higher concentrations (IC50 = 0.66 M; IC50 = 0.58 M,

␤

activity versus c-KIT and PDGFR . Excellent selectiv- respectively). It has some additional activity against c-KIT

␮

ity for KDR was evident, with IC50 < 1 nmol/L, whereas and c-FMS (IC50 = 0.73 M; IC50 = 1.4 ␮M) [88]. In pre-

the IC50 values for VEGFR1/Flt-1, VEGFR3/Flt-4, c-KIT clinical models, vatalanib caused a signiﬁcant decrease in

and PDGFR␤ were 5 nmol/L, ≤3 nmol/L, 2 nmol/L and vessel permeability, reduction in tumor vessel density and

5 nmol/L, respectively [80]. Cediranib was found more potent repression of tumor growth with high efﬁcacy, though the

against VEGF-induced HUVEC proliferation than other inhibition of VEGFRs [88–90]. Phases I and II clinical studies

VEGFR TKIs that are currently under clinical trials, includ- have evaluated the biological activity of vatalanib in several

ing vatalanib and sunitinib [81]. Cediranib promoted the advanced solid tumors known to overexpress VEGF and its

reduction of tumor growth in a mouse model of spontaneous receptors, such as metastatic gastrointestinal tumors, renal

intestinal cancer [81] and blocked both ligand- and tumor cell carcinoma and prostate cancer [91–94].

cell-driven angiogenesis and lymphangiogenesis in vivo [82]. In a recent phase I study of vatalanib for the treatment

A ﬁrst clinical study was carried out to determine the of primary refractory or relapsed AML, 5 out of 17 patients

safety and tolerability, pharmacokinetic proﬁle of cediranib treated with induction chemotherapy and vatalanib achieved

and evaluation of its efﬁcacy in patients with metastatic or complete remission [95]. Furthermore, an in vitro study

advanced solid tumors refractory to standard treatments [83]. showed that the combined treatment with amsacrine and

Once-daily oral at doses of 45 mg or less was generally well vatalanib might lower the dosage of chemotherapy neces-

tolerated and its effects on tumor growth appeared to be dose- sary to achieve equal levels of AML cells death [96]. In

related. Thereafter, clinical studies have demonstrated that addition, our group showed that combined treatment with

cediranib exhibit potential efﬁcacy either as a monotherapy or vatalanib plus a chemotherapic (idarubicin) in four AML cell

in combination with chemotherapy, radiotherapy or other bio- lines and freshly isolated AML blasts had a potent inhibitory

logical agents in many solid tumors, including lung, prostate, effect on the cell proliferation, apoptosis and angiogenesis

breast, renal, ovarian and colorectal cancers (reviewed in [84]. [97].

Cediranib is currently in phase II/phase III clinical develop-

ment. 2.2.10. Vandetanib (ZD6474)

Despite its efﬁcacy in solid tumors, cediranib had little Vandetanib is a selective inhibitor of VEGFR, epidermal

evidence for in vitro cytotoxicity in 22 pediatric leukemia growth factor receptor (EGFR) and the RET [98]. This com-

cell lines. More success was demonstrated in vivo when used pound has a potent activity versus the phosphorylation of

against a panel of pediatric tumor xenograft models, sug- VEGFR2/KDR (IC50 = 40 nM) and some additional activ-

gesting a direct effect on tumor vasculature rather than tumor ity versus VEGFR3 (IC50 = 110 nM), EGFR (IC50 = 500 nM)

cells. Thus, this study do not support a therapeutically rele- and VEGFR1 (IC50 = 1600 nM) [99]. The potent activity

vant effect for cediranib in the pediatric acute lymphocytic of vandetanib against VEGFR2 turned into an inhibition

leukemia setting, most likely due to toxic effects of anti- of VEGF signalling in endothelial cells. In vitro studies

A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256 249

demonstrated the ability of vandetanib to inhibit tumor- through the inhibition of VEGFR2. The dual inhibition of

induced neovascularization and growth of human tumor EGFR and VEGFR phosphorylation by AEE788 reduced

xenograft models, despite their histological origins (breast, the growth, and induced apoptosis of hepatocellular carci-

lung, prostate, colon, ovary, and vulva) [99]. Moreover, in noma cells. Moreover, in a subcutaneous xenograft model,

vivo analysis showed that vandetanib reversed the effects AEE788 decreased tumor growth by reducing prolifera-

induced by VEGF in rats, but does not signiﬁcantly alter the tion and vascularisation [103]. In others in vitro studies,

effects promoted by bFGF. These data supported the selective AEE788 profoundly blocked the interaction of renal cell

action of vandetanib in VEGF signal. carcinoma (RCC) cells with endothelium and extracellu-

Phase I trials have shown that vandetanib is well toler- lar matrix and reduced tumor growth [104]. This drug is

ated as a single agent at daily doses <300 mg. Thereafter, being evaluated in phase I studies in patients with advanced

vandetanib was evaluated in phase II clinical trials in several solid tumors [105–107] and with recurrent glioblastoma

tumors types, including non-small cell lung cancer (NSCLC), [108].

small cell lung cancer (SCLC), breast cancer and multiple Recently, we have analyzed the effects of AEE788 in the

myeloma. Phase III clinical studies are currently being con- cell survival of three AML cell lines: THP-1, MOLM-13 and

ducted in NSCLC (reviewed in [100]). MV4-11, as well as AML blasts. Moreover, we analyzed the

Two recent in vitro studies have shown the effects of activation VEGF/VEGFRs loop, FLT3 and their downstream

vandetanib in several myeloid leukemia cell lines [40,101]. effectors. AEE788 abrogated VEGFRs activation and many

This compound induced growth arrest and apoptosis of EOL- survival signaling pathways, including Akt, ERK, STAT5 and

␬

1, MV4-11 and kasumi-1 cells (which harbour activating NF- B. This compound also acted as a FLT3 and had an

mutations in PDGFR␣, FLT3 and c-KIT), by inhibiting antiproliferative and proapoptotic activity in AML-derived

the phosphorylation of these receptors and blocking their cell lines that endogenously expressed an activated FLT3

downstream effectors (ERK, Akt and STAT3). In addition, receptor. Taken together, our results suggested that AEE788

vandetanib treatment was active against freshly isolated AML might represent a new promising therapy for the treatment of

blasts that had FLT3 mutations, supporting the use of van- AML patients [109].

detanib in AML that possess mutations in receptor tyrosine

kinase genes [40]. 2.3. Statins

2.2.11. AEE788 Statins are 3-hydroxy-3-methylglutaryl-CoA reductase

AEE788 is a novel synthesized, oral small-molecule TKI inhibitors, blocking the mevalonate pathway and its down-

of both EGFR and VEGFR [102]. At the enzyme level, stream products such as cholesterol. Lovastatin, pravastatin,

AEE788 inhibit EGFR and VEGFRs in the nM range (IC50s: simvastatin, ﬂuvastatin, atorvastatin, cerivastatin, pitavas-

EGFR 2 nM, VEGFR2 77 nM, and VEGFR1 59 nM). tatin and rosuvastatin are currently commercially available

In vivo and in vitro studies showed that AEE788 (Fig. 3). These drugs decrease hepatic cholesterol pro-

strongly inhibited phosphorylation of MAPK and Akt duction, which leads to increased LDL receptor turnover,

Fig. 3. Chemical structures of statins.

250 A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256

enhanced hepatic LDL-cholesterol uptake, and ultimately drug [123]. The combination of simvastatin with farnesyl-

decreased plasma LDL-cholesterol levels. The lowering of transferase inhibitors was also beneﬁcial in the treatment of

serum cholesterol levels is therefore thought to be the pri- AML, although this treatment caused differential responses

mary mechanism underlying the therapeutic beneﬁts of statin depending on the AML CD34 (+) and CD34 (−) subfractions

therapy in cardiovascular disease. [124].

Moreover, by inhibiting HMG-CoA reductase, statins can Pravastatin was tested in a phase I study in which it was

also inhibit the synthesis of isoprenoids, which are impor- combined with idarubicin and high-dose cytarabine. Rhab-

tant lipid attachments for intracellular signaling molecules, domyolysis is a prominent and severe effect of these drugs.

such as Rho GTPase family (Rho, Rac and Cdc42). Each Thus, the application of very high doses of statins has to be

member of the Rho GTPase family serves speciﬁc functions taken into consideration. This work showed tolerable toxicity

in terms of cell shape, motility, secretion and proliferation. at very high doses of pravastatin. High response rates for both

The pleiotropic effects of statins might due to the wide range newly diagnosed patients with poor prognosis and for sal-

of Rho GTPase proteins functions. Thus, Rho is associated vage patients were demonstrated. Moreover, the addition of

with stress ﬁber formation, cytoskeletal regulation, cell cycle pravastatin to conventional chemotherapy blocked the choles-

regulation, signal transduction, proliferation and migration, terol increase, which is usually produced in AML blasts after

and eNOS and NO regulation; Rac1 is involved in cytoskele- chemotherapy. The authors encourage future phase II studies

tal regulation, superoxide production, oncogenesis, Map3K [125].

activation and Pak activation and ﬁnally CDc42 is related In an effort to ﬁnd effective therapies for the treatment of

to cytoskeletal regulation and signal transduction (reviewed acute promyelocytic leukemia (APL), statins have been tested

in [110]). Statins might affect vascular function through the to overcome the development of ATRA resistance by APL

modulation of these signaling proteins that depend on post- cells. Recently, it was evaluated the antileukemic spectrum

translational modiﬁcation with isoprenoid. Indeed, several of various statins for chemotherapic use in ATRA resistant

studies suggest that statins might be involved in immunomod- APL. In this study it was found that ﬂuvastatin enhanced the

ulation [111], neuroprotection [112] and cellular senescence differentiation induced by ATRA and consequently enhanced

[113]. the cytotoxic effect of ATRA in APL cells [126]. Thereafter

Recently, there is emerging interest in their use as anti- another study revealed that simvastatin had an unique mech-

neoplastic agents, due to their antiproliferative, anti-invasive anism that causes apoptosis via mitochondrial dysfunction,

and proapoptosis effects (reviewed in [114]). Moreover, it followed by the caspase-9-related cascade, and thus it might

is possible that statins may modulate angiogenesis in a be useful solely for the anti-leukemic therapy in APL [127].

therapeutic manner, enhancing endothelial functions. It has Most of these works described above have been performed

been shown that statins possess dose-dependent effects on in AML cell lines or blasts, thus supporting the need for fur-

angiogenesis. Statins reduced tumor growth and inhibited ther evaluation of statins in clinical trials for the treatment of

VEGFR2 expression at high (micromolar) concentrations, AML.

while enhanced angiogenesis at low (nanomolar) concentra-

tions [115]. Several studies have reported that statins decrease 2.4. Arsenic trioxide

VEGF synthesis in different cell types, including tumor cells

[115–117]. Arsenic has been used for centuries to treat a wide vari-

In vitro, statins induce apoptosis in both primary and ety of diseases. Arsenic trioxide (ATO) has been shown to

tumor cells derived from patients with a variety of malig- have multiple biological effects, including depletion of cel-

nancies [116]. Recently, several studies have suggested the lular thiols, disruption of mitochondrial respiration, induction

possible use of statins in therapy for AML [118,119]. The of apoptosis and antiproliferative activity [128]. Concretely,

ﬁrst studies that supported the therapeutic potential of statins ATO induces apoptosis via changes in the mitochondrial

in the treatment of the AML were performed with lovas- membrane potential. This compound produces an increase of

tatin and simvastatin. In vitro studies in AML cell lines intracellular levels of hydrogen peroxide, lowering mitochon-

showed that lovastatin induced a differentiation response drial membrane potential and leading to cytochrome c release

and cytotoxicity at physiological concentrations of this agent and subsequent caspase pathway activation. Moreover, ATO

[120,121] and in a short term [122]. Moreover, the com- induces the expression of bax which down regulates the

bination of lovastatin with other agents such as tyrosine expression of bcl-2 family members and inhibits the NF-

kinase inhibitors might potentiate their cytotoxic effects ␬B activation. This compound also promotes the recruitment

[118]. Regarding in vivo studies, high dose of lovastatin sup- of PML onto matrix-bound nuclear bodies for degradation,

pressed blast cell growth in an elderly patient with AML which contribute to the induction of apoptosis. In the other

[119]. hand, its antiproliferative capacity is due to the growth arrest

On the other hand, it has been shown that simvastatin in the G1 phase of the cell cycle, inhibition of STAT3

has great antiproliferative effect on AML blasts in vitro and activity and the induction of the cell differentiation though

that the combined treatment with simvastatin plus ARA-C the induction of CD11b maturation marker (reviewed in

signiﬁcantly enhanced the antiproliferative effect of each [128]).

A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256 251

ATO may additionally affect tumor cell growth by inhibit- patients. These targets would include FLT3, KIT and VEGF

ing angiogenesis. In a mouse model with a solid tumor, signalling. Inhibitors that block simultaneously the signalling

ATO induced preferential vascular shutdown in tumor tis- induced by these molecules at lower concentrations have

sue, so that the central part of the tumor showed massive the possibility of being more effective in the treatment of

necrosis, whereas normal vasculature remained relatively AML, since they are capable of inhibiting both the angio-

unaffected [129]. Thereafter, treatment of leukemic cells with genesis and the cell proliferation. Moreover, it is important

ATO has been shown to produce a down-regulation of VEGF to note that the combination of these new therapies based

expression, culminating in apoptosis. Moreover, the recipro- on the inhibition of angiogenesis with cytotoxic agents that

cal stimulatory loop between leukemic cells and endothelial work independently on different cellular targets is turning

cells was blocked [130]. The antileukemic activity of ATO out into an effective treatment for AML. In this way, lestau-

has been widely studied in the APL subtype of AML. It has rtinib and midostaurin are the two multi-receptor tyrosine

been shown that ATO is useful for the treatment of resistant kinase inhibitors that are in phase III trials, and combined with

or relapsed cases of APL after treatment with ATRA [131]. chemotherapy have showed good results, achieving complete

The main mechanisms of action involved in the responsive- remissions.

ness of leukemic promyelocytes to ATO include activation The effects of many of the described inhibitors also depend

of the apoptotic caspase cascade, induction of differentiation on the speciﬁc cellular and molecular proﬁle of each AML

and reduction of microvascular density of bone marrow. Cur- patient, such as the levels of VEGF/VEGFRs expression,

rently, ATO is being used as a single agent as initial therapy or the positivity for the FLT3/ITD mutation, which should

in APL. Single-agent ATO in untreated APL, showed a very also be analyzed and taken into account prior to the admin-

high clinical and a reasonably good molecular remission rate istration of those compounds. Another relevant aspect to

[132]. In addition, several studies have shown the beneﬁt of consider when developing new drugs should be not only their

ATO in both the induction and the consolidation therapy in speciﬁcity in terms of angiogenesis, proliferation or tyrosine

this AML subtype [133,134]. kinase inhibition, but also the adverse effects caused in AML

There is evidence that the effects of ATO are not restricted patients, either given alone or in combination with standard

to events speciﬁc for APL. In vitro studies have demonstrated chemotherapy, an aspect that has provoked the stopping of

that ATO have antiproliferative and apoptotic effects on a many clinical trials. Thus, special care should be further taken

variety of AML cell lines at doses that are achievable in in the drug formulation.

vivo [135]. No responses were observed in a phase II trial Taken together, a plethora of new treatment approaches for

with ATO monotherapy in patients with relapse/refractory AML patients has emerged in recent years. All of them have

AML, secondary leukemia, and AML in older adults [136]. shown limited effectiveness, and, in a similar way to what

However, several studies have suggested that the combina- happened with the ‘traditional treatments’ administered to

tion therapy with ATO and molecules capable of inhibiting AML patients, showed a number of adverse effects. Neverthe-

tyrosine kinase proteins may lead to improved ATO efﬁcacy less, the knowledge continues increasing, and there are two

against AML. In vitro studies in blasts from 25 patients with lessons to learn from the experience to date: (1) that no single

different subtypes of AML showed that combination of ATO treatment is effective and safe enough and (2) that every single

with an inhibitor of MEK/ERK pathway greatly enhanced patient shows a cellular and molecular proﬁle that physicians

the apoptosis of these cells [137]. Other work demonstrated should seriously take into consideration. As there are still

a synergistic growth-inhibitory effect for the combination of cases in which the remissions are partial or patients develop

ATO and a chemical inhibitor of FLT3 phosphorylation in resistance to the treatment, others antiangiogenic drugs that

AML FLT3/ITD cell lines [138]. Clinical data have shown block the interaction of VEGF with its receptors, or acting

that the combination of ATO with low-dose cytarabine or as tyrosine kinase inhibitors, or indirectly inhibiting VEGF,

ascorbic acid improved responses in AML elderly patients remains to be developed that deserve further evaluation in

compared with either agent alone [139,140]. Overall stud- prospective clinical trials.

ies suggest that ATO deserves further clinical study in the

treatment of AML.

Conﬂict of interest

3. Conclusions The authors reported no conﬂict of interest.

As multiple signal transduction pathways are activated in

AML, just a molecular targeted therapy is unlikely to be cura- Reviewers

tive if used alone. Although lately VEGF have brought up

much attention in the pathology of AML, there is evidence Bianca F. Goemans, M.D., Post-doctoral fellow, VU

that its only inhibition is not as effective as it was ﬁrstly University Medical Center, Department of Pediatric

thought. The responses are modest and transient. Thus, simul- Oncology/Hematology, De Boelelaan 1117, NL-1081 HV

taneous inhibition of multiple targets is necessary in most Amsterdam, Netherlands.

252 A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256

Seiji Fukuda, M.D., Associate Professor, Shimane Uni- [18] Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor

signalling—in control of vascular function. Nat Rev Mol Cell Biol

versity School of Medicine, Department of Pediatrics, 89-1

2006;7:359–71.

Enya-cho, Izumo city, Shimane 693-0021, Japan.

[19] Takahashi T, Yamaguchi S, Chida K, Shibuya M. A single autophos-

phorylation site on KDR/Flk-1 is essential for VEGF-A-dependent

activation of PLC-gamma and DNA synthesis in vascular endothelial

Acknowledgement cells. EMBO J 2001;20:2768–78.

[20] Holmqvist K, Cross MJ, Rolny C, et al. The adaptor protein shb

binds to tyrosine 1175 in vascular endothelial growth factor (VEGF)

This work was supported by grants from Junta de Andalu-

receptor-2 and regulates VEGF-dependent cellular migration. J Biol cia (JA0030/2007), Spain.

Chem 2004;279:22267–75.

[21] Lamalice L, Houle F, Huot J. Phosphorylation of Tyr1214 within

VEGFR-2 triggers the recruitment of Nck and activation of Fyn

References leading to SAPK2/p38 activation and endothelial cell migration in

response to VEGF. J Biol Chem 2006;281:34009–20.

[1] Grimwade D. The clinical signiﬁcance of cytogenetic abnormal- [22] Bellamy WT, Richter L, Sirjani D, et al. Vascular endothelial

ities in acute myeloid leukaemia. Best Pract Res Clin Haematol cell growth factor is an autocrine promoter of abnormal localized

2001;14:497–529. immature myeloid precursors and leukemia progenitor formation in

[2] Kelly LM, Gilliland DG. Genetics of myeloid leukemias. Annu Rev myelodysplastic syndromes. Blood 2001;97:1427–34.

Genomics Hum Genet 2002;3:179–98. [23] Podar K, Tai YT, Davies FE, et al. Vascular endothelial growth factor

[3] Tobal K, Pagliuca A, Bhatt B, Bailey N, Layton DM, Mufti GJ. triggers signaling cascades mediating multiple myeloma cell growth

Mutation of the human FMS gene (M-CSF receptor) in myelodys- and migration. Blood 2001;98:428–35.

plastic syndromes and acute myeloid leukemia. Leukemia 1990;4: [24] Dias S, Shmelkov SV, Lam G, Raﬁi S. VEGF(165) promotes survival

486–9. of leukemic cells by Hsp90-mediated induction of Bcl-2 expression

[4] Gari M, Goodeve A, Wilson G, et al. c-kit proto-oncogene exon 8 in- and apoptosis inhibition. Blood 2002;99:2532–40.

frame deletion plus insertion mutations in acute myeloid leukaemia. [25] Barbarroja N, Aristides-Torres L, Hernandez V, et al. Coordinated

Br J Haematol 1999;105:894–900. deregulation of cellular receptors, proangiogenic factors and intra-

[5] Care RS, Valk PJ, Goodeve AC, et al. Incidence and prognosis of c- cellular pathways in acute myeloid leukaemia. Leuk Lymphoma

KIT and FLT3 mutations in core binding factor (CBF) acute myeloid 2007;48:1187–99.

leukaemias. Br J Haematol 2003;121:775–7. [26] Aguayo A, Estey E, Kantarjian H, et al. Cellular vascular endothelial

[6] Choudhary C, Schwable J, Brandts C, et al. AML-associated Flt3 growth factor is a predictor of outcome in patients with acute myeloid

kinase domain mutations show signal transduction differences com- leukemia. Blood 1999;94:3717–21.

pared with Flt3 ITD mutations. Blood 2005;106:265–73. [27] Presta LG, Chen H, O’Connor SJ, et al. Humanization of an

[7] Meshinchi S, Appelbaum FR. Structural and functional alterations of anti-vascular endothelial growth factor monoclonal antibody for

FLT3 in acute myeloid leukemia. Clin Cancer Res 2009;15:4263–9. the therapy of solid tumors and other disorders. Cancer Res

[8] Minami Y, Kiyoi H, Yamamoto Y, et al. Selective apoptosis of 1997;57:4593–9.

tandemly duplicated FLT3-transformed leukemia cells by Hsp90 [28] Mukherji SK. Bevacizumab (Avastin). AJNR Am J Neuroradiol

inhibitors. Leukemia 2002;16:1535–40. 2010;(2):235–6.

[9] Zheng R, Levis M, Piloto O, et al. FLT3 ligand causes autocrine [29] Zahiragic L, Schliemann C, Bieker R, et al. Bevacizumab reduces

signaling in acute myeloid leukemia cells. Blood 2004;103: VEGF expression in patients with relapsed and refractory acute

267–74. myeloid leukemia without clinical antileukemic activity. Leukemia

[10] Siendones E, Barbarroja N, Torres LA, et al. Inhibition of Flt3- 2007;21:1310–2.

activating mutations does not prevent constitutive activation of [30] Karp JE, Gojo I, Pili R, et al. Targeting vascular endothelial growth

ERK/Akt/STAT pathways in some AML cells: a possible cause for the factor for relapsed and refractory adult acute myelogenous leukemias:

limited effectiveness of monotherapy with small-molecule inhibitors. therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitox-

Hematol Oncol 2007;25:30–7. antrone, and bevacizumab. Clin Cancer Res 2004;10:3577–85.

[11] Ribatti D, Vacca A, Presta M. The discovery of angiogenic factors: a [31] Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intra-

historical review. Gen Pharmacol 2000;35:227–31. venous vascular endothelial growth factor trap, aﬂibercept, in patients

[12] Carmeliet P. Angiogenesis in life, disease and medicine. Nature with advanced solid tumors. J Clin Oncol 2010;28:207–14.

2005;438:932–6. [32] Zhu Z, Hattori K, Zhang H, et al. Inhibition of human leukemia in

[13] Hussong JW, Rodgers GM, Shami PJ. Evidence of increased an animal model with human antibodies directed against vascular

angiogenesis in patients with acute myeloid leukemia. Blood endothelial growth factor receptor 2. Correlation between antibody

2000;95:309–13. afﬁnity and biological activity. Leukemia 2003;17:604–11.

[14] Padro T, Ruiz S, Bieker R, et al. Increased angiogenesis in the [33] Sakamoto KM. Su-11248 Sugen. Curr Opin Investig Drugs

bone marrow of patients with acute myeloid leukemia. Blood 2004;5:1329–39.

2000;95:2637–44. [34] Vroling L, van der Veldt AAM, de Haas RR, et al. Increased num-

[15] Hicklin DJ, Ellis LM. Role of the vascular endothelial growth bers of small circulating endothelial cells in renal cell cancer patients

factor pathway in tumor growth and angiogenesis. J Clin Oncol treated with sunitinib. Angiogenesis 2009;12:69–79.

2005;23:1011–27. [35] Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary

[16] Keyt BA, Berleau LT, Nguyen HV, et al. The carboxyl-terminal kinase genotypes correlate with the biological and clinical activity of

domain (111–165) of vascular endothelial growth factor is critical sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin

for its mitogenic potency. J Biol Chem 1996;271:7788–95. Oncol 2008;26:5352–9.

[17] List AF, Glinsmann-Gibson B, Stadheim C, Meuillet EJ, Bel- [36] O’Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3

lamy W, Powis G. Vascular endothelial growth factor receptor-1 tyrosine kinase inhibitor with potent activity in vitro and in vivo.

and receptor-2 initiate a phosphatidylinositide 3-kinase-dependent Blood 2003;101:3597–605.

clonogenic response in acute myeloid leukemia cells. Exp Hematol [37] Fiedler W, Serve H, Dohner H, et al. A phase 1 study of SU11248

2004;32:526–35. in the treatment of patients with refractory or resistant acute myeloid

A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256 253

leukemia (AML) or not amenable to conventional therapy for the hypoxia in RCC xenograft models. Cancer Chemother Pharmacol

disease. Blood 2005;105:986–93. 2007;59:561–74.

[38] O’Farrell AM, Foran JM, Fiedler W, et al. An innovative phase [56] Rahmani M, Davis EM, Bauer C, Dent P, Grant S. Apoptosis induced

I clinical study demonstrates inhibition of FLT3 phosphorylation by the kinase inhibitor BAY 43-9006 in human leukemia cells involves

by SU11248 in acute myeloid leukemia patients. Clin Cancer Res down-regulation of Mcl-1 through inhibition of translation. J Biol

2003;9:5465–76. Chem 2005;280:35217–27.

[39] Yee KW, Schittenhelm M, O’Farrell AM, et al. Synergistic effect [57] Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepa-

of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive tocellular carcinoma. N Engl J Med 2008;359:378–90.

leukemic cells. Blood 2004;104:4202–9. [58] Delmonte J, Kantarjian HM, Andreeff M, et al. Update of a

[40] Nishioka C, Ikezoe T, Takeshita A, et al. ZD6474 induces growth phase I study of sorafenib in patients with refractory/relapsed acute

arrest and apoptosis of human leukemia cells, which is enhanced myeloid leukemia or high-risk myelodysplastic syndrome. Blood

by concomitant use of a novel MEK inhibitor, AZD6244. Leukemia 2007;110:893.

2007;21:1308–10. [59] Zhang W, Konopleva M, Shi YX, et al. Mutant FLT3: a direct tar-

[41] Smolich BD, Yuen HA, West KA, Giles FJ, Albitar M, Cherrington get of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst

JM. The antiangiogenic protein kinase inhibitors SU5416 and SU6668 2008;100:184–98.

inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line [60] Safaian NN, Czibere A, Bruns I, et al. Sorafenib (Nexavar) induces

and in acute myeloid leukemia blasts. Blood 2001;97:1413–21. molecular remission and regression of extramedullary disease in

[42] Yee KW, O’Farrell AM, Smolich BD, et al. SU5416 and SU5614 a patient with FLT3–ITD+ acute myeloid leukemia. Leuk Res

inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine 2009;33:348–50.

kinase. Blood 2002;100:2941–9. [61] Metzelder S, Wang Y, Wollmer E, et al. Compassionate use of

[43] Fong TA, Shawver LK, Sun L, et al. SU5416 is a potent and selective sorafenib in FLT3–ITD-positive acute myeloid leukemia: sustained

inhibitor of the vascular endothelial growth factor receptor (Flk- regression before and after allogeneic stem cell transplantation. Blood

1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, 2009;113:6567–71.

and growth of multiple tumor types. Cancer Res 1999;59:99–106. [62] Levis M, Allebach J, Tse KF, et al. A FLT3-targeted tyrosine kinase

[44] Loges S, Tinnefeld H, Metzner A, et al. Downregulation of VEGF-A, inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood

STAT5 and AKT in acute myeloid leukemia blasts of patients treated 2002;99:3885–91.

with SU5416. Leuk Lymphoma 2006;47:2601–9. [63] Smith BD, Levis M, Beran M, et al. Single-agent CEP-701,

[45] Fiedler W, Mesters R, Tinnefeld H, et al. A phase 2 clinical study of a novel FLT3 inhibitor, shows biologic and clinical activity in

SU5416 in patients with refractory acute myeloid leukemia. Blood patients with relapsed or refractory acute myeloid leukemia. Blood

2003;102:2763–7. 2004;103:3669–76.

[46] O’Farrell AM, Yuen HA, Smolich B, et al. Effects of SU5416, a small [64] Chan E, Mulkerin D, Rothenberg M, et al. A phase I trial of CEP-

molecule tyrosine kinase receptor inhibitor, on FLT3 expression and 701+ gemcitabine in patients with advanced adenocarcinoma of the

phosphorylation in patients with refractory acute myeloid leukemia. pancreas. Invest New Drugs 2008;26:241–7.

Leuk Res 2004;28:679–89. [65] Knapper S, Burnett AK, Littlewood T, et al. A phase 2 trial of the

[47] Salzberg M, Pless M, Rochlitz C, Ambrus K, Scigalla P, Herrmann FLT3 inhibitor lestaurtinib (CEP701) as ﬁrst-line treatment for older

R. A phse I study with oral SU5416 in patients with advanced patients with acute myeloid leukemia not considered ﬁt for intensive

solid tumors: a drug inducing its clearance. Invest New Drugs chemotherapy. Blood 2006;108:3262–70.

2006;24:299–304. [66] Knapper S, Mills KI, Gilkes AF, Austin SJ, Walsh V, Burnett AK.

[48] Giles FJ, Stopeck AT, Silverman LR, et al. SU5416, a small molecule The effects of lestaurtinib (CEP701) and PKC412 on primary AML

tyrosine kinase receptor inhibitor, has biologic activity in patients with blasts: the induction of cytotoxicity varies with dependence on

refractory acute myeloid leukemia or myelodysplastic syndromes. FLT3 signaling in both FLT3-mutated and wild-type cases. Blood

Blood 2003;102:795–801. 2006;108:3494–503.

[49] Sun L, Tran N, Tang F, et al. Synthesis and biological evaluations of 3- [67] Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3

substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors inhibitor combined with chemotherapy: sequence of administra-

that exhibit selectivity toward particular receptor tyrosine kinases. J tion is important to achieve synergistic cytotoxic effects. Blood

Med Chem 1998;41:2588–603. 2004;104:1145–50.

[50] Spiekermann K, Faber F, Voswinckel R, Hiddemann W. The protein [68] Fabbro D, Ruetz S, Bodis S, et al. PKC412—a protein kinase

tyrosine kinase inhibitor SU5614 inhibits VEGF-induced endothelial inhibitor with a broad therapeutic potential. Anticancer Drug Des

cell sprouting and induces growth arrest and apoptosis by inhibition 2000;15:17–28.

of c-kit in AML cells. Exp Hematol 2002;30:767–73. [69] Millward MJ, House C, Bowtell D, et al. The multikinase inhibitor

[51] Aleskog A, Hoglund M, Pettersson J, Hermansson M, Larsson R, midostaurin (PKC412A) lacks activity in metastatic melanoma: a

Lindhagen E. In vitro activity of the ﬂt3-inhibitor su5614 and standard phase IIA clinical and biologic study. Br J Cancer 2006;95:829–

cytotoxic agents in tumour cells from patients with wild type and 34.

mutated ﬂt3 acute myeloid leukaemia. Leuk Res 2005;29:1079–81. [70] Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute

[52] Arseni N, Ahmed F, Hiddemann W, Buske C, Feuring-Buske M. myeloid leukemia and an activating mutation in FLT3 respond to

Effects of the protein tyrosine kinase inhibitor, SU5614, on leukemic a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood

and normal stem cells. Haematologica 2005;90:1577–8. 2005;105:54–60.

[53] von Bubnoff N, Engh RA, Aberg E, Sanger J, Peschel C, Duyster [71] Levis M, Stine A, Pham R, et al. Pharmacokinetic and phar-

J. FMS-like tyrosine kinase 3-internal tandem duplication tyrosine macodynamic studies of lestaurtinib (CEP-701) and PKC412:

kinase inhibitors display a nonoverlapping proﬁle of resistance muta- cytotoxicity is often dependent on non-FLT3 mediated effects. Blood

tions in vitro. Cancer Res 2009;69:3032–41. 2005;106:692a.

[54] Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad [72] George P, Bali P, Cohen P, et al. Cotreatment with 17-allylamino-

spectrum oral antitumor activity and targets the RAF/MEK/ERK path- demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is

way and receptor tyrosine kinases involved in tumor progression and highly effective against human acute myelogenous leukemia cells

angiogenesis. Cancer Res 2004;64:7099–109. with mutant FLT-3. Cancer Res 2004;64:3645–52.

[55] Chang YS, Adnane J, Trail PA, et al. Sorafenib (BAY 43-9006) inhibits [73] Bali P, George P, Cohen P, et al. Superior activity of the combina-

tumor growth and vascularization and induces tumor apoptosis and tion of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase

254 A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256

inhibitor PKC412 against human acute myelogenous leukemia cells tional vascular properties as detected by dynamic enhanced magnetic

with mutant FLT-3. Clin Cancer Res 2004;10:4991–7. resonance imaging. Cancer Res 2002;62:4015–22.

[74] Mohi MG, Boulton C, Gu TL, et al. Combination of rapamycin [91] Joensuu H, De BF, Coco P, et al. Phase II, open-label study

and protein tyrosine kinase (PTK) inhibitors for the treatment of of PTK787/ZK222584 for the treatment of metastatic gastroin-

leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA testinal stromal tumors resistant to imatinib mesylate. Ann Oncol

2004;101:3130–5. 2008;19:173–7.

[75] Stone RM, Fischer T, Paquette R, et al. Phase 1B study of PKC412, an [92] Sharma S, Freeman B, Turner J, et al. A phase I trial of

oral FLT3 kinase inhibitor, in sequential and simultaneous combina- PTK787/ZK222584 in combination with pemetrexed and cisplatin

tions with daunorubicin and cytarabine (DA) induction and high-dose in patients with advanced solid tumors. Invest New Drugs 2009;27:

cytarabine ansolidation in newly diagnosed adult patients (PTS) 63–5.

with acute myeloid leukemia (AML) under age. Blood 2006;61:108 [93] George D, Jonasch E, Hart L, et al. A phase I, dose escalating

[abstract 157]. and pharmacokinetic (PK) study of the VEGF-receptor inhibitor

[76] Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangio- PTK787/ZK222584 (PTK/ZK) in patients with advanced renal cell

genesis and antitumor activities of axitinib (AG-013736), an oral, or prostate carcinomas. Clin Cancer Res 2001;7:548a.

potent, and selective inhibitor of vascular endothelial growth fac- [94] George D, Michaelson D, Oh WK, et al. Phase I study of PTK787/ZK

tor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 2008;14: 222584 (PTK/ZK) in metastatic renal cell carcinoma. Proc Am Soc

7272–83. Clin Oncol 2003;22:385 [abstract 1548].

[77] Kelly RJ, Rixe O. Axitinib (AG-013736). Recent Results Cancer Res [95] Roboz GJ, Giles FJ, List AF, et al. Phase 1 study of PTK787/ZK

2010;184:33–44. 222584, a small molecule tyrosine kinase receptor inhibitor, for the

[78] Giles FJ, Steinfeldt H, Bellamy WT, et al. Phase 2 study of the treatment of acute myeloid leukemia and myelodysplastic syndrome.

anti-angiogenesis agent AG-013736 in patients with poor prognosis Leukemia 2006;20:952–7.

acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). [96] Weidenaar AC, de Jonge HJ, Fidler V, et al. Addition of PTK787/ZK

Blood (ASH Annual Meeting Abstracts) 2004;104 [abstract 1813]. 222584 can lower the dosage of amsacrine to achieve equal amounts

[79] Giles FJ, Bellamy WT, Estrov Z, et al. The anti-angiogenesis agent, of acute myeloid leukemia cell death. Anticancer Drugs 2008;19:45–

AG-013736, has minimal activity in elderly patients with poor prog- 54.

nosis acute myeloid leukemia (AML) or myelodysplastic syndrome [97] Barbarroja N, Torres LA, Luque MJ, et al. Additive effect of

(MDS). Leuk Res 2006;30:801–11. PTK787/ZK 222584, a potent inhibitor of VEGFR phosphorylation,

[80] Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly with Idarubicin in the treatment of acute myeloid leukemia. Exp

potent, orally bioavailable, vascular endothelial growth factor Hematol 2009;37:679–91.

receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer [98] Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally avail-

Res 2005;65:4389–400. able inhibitor of KDR tyrosine kinase activity, efﬁciently blocks

[81] Goodlad RA, Ryan AJ, Wedge SR, et al. Inhibiting vascular endothe- oncogenic RET kinases. Cancer Res 2002;62:7284–90.

lial growth factor receptor-2 signaling reduces tumor burden in the [99] Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular

ApcMin/+ mouse model of early intestinal cancer. Carcinogenesis endothelial growth factor signaling, angiogenesis, and tumor growth

2006;27:2133–9. following oral administration. Cancer Res 2002;62:4645–55.

[82] Heckman CA, Holopainen T, Wirzenius M, et al. The tyrosine [100] Morabito A, Piccirillo MC, Falasconi F, et al. Vandetanib (ZD6474), a

kinase inhibitor cediranib blocks ligand-induced vascular endothe- dual inhibitor of vascular endothelial growth factor receptor (VEGFR)

lial growth factor receptor-3 activity and lymphangiogenesis. Cancer and epidermal growth factor receptor (EGFR) tyrosine kinases: cur-

Res 2008;68:4754–62. rent status and future directions. Oncologist 2009;14:378–90.

[83] Drevs J, Siegert P, Medinger M, et al. Phase I clinical study [101] Jia HY, Wu JX, Zhu XF, et al. ZD6474 inhibits Src kinase leading to

of AZD2171, an oral vascular endothelial growth factor signal- apoptosis of imatinib-resistant K562 cells. Leuk Res 2009;33:1512–9.

ing inhibitor, in patients with advanced solid tumors. J Clin Oncol [102] Traxler P, Allegrini PR, Brandt R, et al. AEE788: a dual family epi-

2007;25:3045–54. dermal growth factor receptor/ErbB2 and vascular endothelial growth

[84] Lindsay CR, MacPherson IR, Cassidy J. Current status of cediranib: factor receptor tyrosine kinase inhibitor with antitumor and antiangio-

the rapid development of a novel anti-angiogenic therapy. Future genic activity. Cancer Res 2004;64:4931–41.

Oncol 2009;5:421–32. [103] Okamoto K, Neureiter D, Alinger B, et al. The dual EGF/VEGF

[85] Fiedler W, Mesters R, Heuser M, et al. Phase I study of cediranib receptor tyrosine kinase inhibitor AEE788 inhibits growth of human

(RECENTIN) in patients with acute myeloid leukemia. Leuk Res hepatocellular carcinoma xenografts in nude mice. Int J Oncol

2010;34:196–202. 2008;33:733–42.

[86] Maris JM, Courtright J, Houghton PJ, et al. Initial testing of the [104] Juengel E, Engler J, Mickuckyte A, et al. Effects of combined valproic

VEGFR inhibitor AZD2171 by the pediatric preclinical testing pro- acid and the epidermal growth factor/vascular endothelial growth fac-

gram. Pediatr Blood Cancer 2008;50:581–7. tor receptor tyrosine kinase inhibitor AEE788 on renal cell carcinoma

[87] Fiedler W, Mesters R, Heuser M, et al. An open-label, Phase I study cell lines in vitro. BJU Int 2010;105:549–57.

of cediranib (RECENTIN) in patients with acute myeloid leukemia. [105] Xiong HQ, Takimoto C, Rojo F, et al. A phase I study of AEE788,

Leuk Res 2010;34:196–202. a multitargeted inhibitor of ErbB and VEGF receptor family tyro-

[88] Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel sine kinases, to determine safety, PK and PD in patients (pts) with

and potent inhibitor of vascular endothelial growth factor receptor advanced colorectal cancer (CRC) and liver metastases. Proc Am Soc

tyrosine kinases, impairs vascular endothelial growth factor-induced Clin Oncol 2007;25:4065.

responses and tumor growth after oral administration. Cancer Res [106] Baselga J, Rojo F, Dumez H, et al. Phase I study of AEE788, a novel

2000;60:2178–89. multitargeted inhibitor of ErbB and VEGF receptor family tyrosine

[89] Hess-Stumpp H, Haberey M, Thierauch KH. PTK 787/ZK 222584, kinases: a pharmacokinetic (PK)-pharmacodynamic (PD) study to

a tyrosine kinase inhibitor of all known VEGF receptors, represses identify the optimal therapeutic dose regimen. Proc Am Soc Clin

tumor growth with high efﬁcacy. Chembiochem 2005;6:550– Oncol 2005;23:3028a.

7. [107] Martinelli E, Takimoto C, Van Oosterom A, et al. AEE788, a novel

[90] Drevs J, Muller-Driver R, Wittig C, et al. PTK787/ZK 222584, a multitargeted inhibitor of ErbB and VEGF receptor family tyrosine

speciﬁc vascular endothelial growth factor-receptor tyrosine kinase kinases: preliminary phase 1 results. Proc Am Soc Clin Oncol 2005

inhibitor, affects the anatomy of the tumor vascular bed and the func- [abstract 3039].

A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256 255

[108] Reardon D, Cloughesy T, Conrad C, et al. A phase I study of [128] Miller Jr WH, Schipper HM, Lee JS, Singer J, Waxman S. Mecha-

AEE788, a novel multitargeted inhibitor of ErbB and VEGF recep- nisms of action of arsenic trioxide. Cancer Res 2002;62:3893–903.

tor family tyrosine kinases, in recurrent GBM patients. J Clin Oncol [129] Lew YS, Brown SL, Grifﬁn RJ, Song CW, Kim JH. Arsenic tri-

2005;23(16S):3063. oxide causes selective necrosis in solid murine tumors by vascular

[109] Barbarroja N, Torres LA, Rodriguez-Ariza A, et al. AEE788 is a vas- shutdown. Cancer Res 1999;59:6033–7.

cular endothelial growth factor receptor tyrosine kinase inhibitor with [130] Roboz GJ, Dias S, Lam G, et al. Arsenic trioxide induces

antiproliferative and proapoptotic effects in acute myeloid leukemia. dose- and time-dependent apoptosis of endothelium and may

Exp Haematol 2010;(April) [Epub ahead of print]. exert an antileukemic effect via inhibition of angiogenesis. Blood

[110] Wang CY, Liu PY, Liao JK. Pleiotropic effects of statin ther- 2000;96:1525–30.

apy: molecular mechanisms and clinical results. Trends Mol Med [131] Niu C, Yan H, Yu T, et al. Studies on treatment of acute

2008;14(January (1)):37–44. promyelocytic leukemia with arsenic trioxide: remission induction,

[111] Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune follow-up, and molecular monitoring in 11 newly diagnosed and

disease: from protein crenulations to immunomodulation. Nat Rev 47 relapsed acute promyelocytic leukemia patients. Blood 1999;94:

Immunol 2006;6:358–70. 3315–24.

[112] Kivipelto M, Solomon A, Winblad B. Statin therapy in Alzheimer’s [132] Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of

disease. Lancet Neurol 2005;4:521–2. acute promyelocytic leukemia with arsenic trioxide without ATRA

[113] Brouilette SW, Moore JS, McMahon AD, et al. Telomere length, risk and/or chemotherapy. Ann Oncol 2006;17:131–4.

of coronary heart disease, and statin treatment in the West of Scot- [133] Powell BL, Moser B, Stock W, et al. Effect of consolidation with

land Primary Prevention Study: a nested case–control study. Lancet arsenic trioxide (As2O3) on event-free survival (EFS) and overall sur-

2007;369:107–14. vival (OS) among patients with newly diagnosed acute promyelocytic

[114] Chan KK, Oza AM, Siu LL. The statins as anticancer agents. Clin leukemia (APL): North American Intergroup Protocol C9710. J Clin

Cancer Res 2003;9:10–9. Oncol 2007;25:1s.

[115] Frick M, Dulak J, Cisowski J, et al. Statins differentially regulate vas- [134] Liu YF, Zhu YM, Shi ZZ, et al. Long-term follow-up conﬁrms the ben-

cular endothelial growth factor synthesis in endothelial and vascular eﬁt of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) as

smooth muscle cells. Atherosclerosis 2003;170:229–36. front line therapy for newly diagnosed acute promyelocytic leukemia

[116] Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic (APL). Blood 2006;108:170a.

effects on angiogenesis. Circulation 2002;105:739–45. [135] Rojewski MT, Baldus C, Knauf W, Thiel E, Schrezenmeier H.

[117] Feleszko W, Balkowiec EZ, Sieberth E, et al. Lovastatin and tumor Dual effects of arsenic trioxide (As2O3) on non-acute promyelocytic

necrosis factor-alpha exhibit potentiated antitumor effects against leukaemia myeloid cell lines: induction of apoptosis and inhibition of

Ha-ras-transformed murine tumor via inhibition of tumor-induced proliferation. Br J Haematol 2002;116:555–63.

angiogenesis. Int J Cancer 1999;81:560–7. [136] Parmar S, Rundhaugen LM, Boehlke L, et al. Phase II trial of arsenic

[118] Wu J, Wong WW, Khosravi F, Minden MD, Penn LZ. Block- trioxide in relapsed and refractory acute myeloid leukemia, secondary

ing the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia and/or newly diagnosed patients at least 65 years old. Leuk

leukemia cells to lovastatin-induced apoptosis. Cancer Res 2004;64: Res 2004;28:909–19.

6461–8. [137] Lunghi P, Costanzo A, Salvatore L, et al. MEK1 inhibition sensi-

[119] Minden MD, Dimitroulakos J, Nohynek D, Penn LZ. Lovastatin tizes primary acute myelogenous leukemia to arsenic trioxide-induced

induced control of blast cell growth in an elderly patient with acute apoptosis. Blood 2006;107:4549–53.

myeloblastic leukemia. Leuk Lymphoma 2001;40:659–62. [138] Takahashi S, Harigae H, Yokoyama H, et al. Synergistic effect of

[120] Dimitroulakos J, Nohynek D, Backway KL, et al. Increased sensi- arsenic trioxide and ﬂt3 inhibition on cells with ﬂt3 internal tandem

tivity of acute myeloid leukemias to lovastatin-induced apoptosis: a duplication. Int J Hematol 2006;84:256–61.

potential therapeutic approach. Blood 1999;93:1308–18. [139] Roboz GJ, Ritchie EK, Curcio T, et al. Arsenic trioxide and low-dose

[121] Dimitroulakos J, Thai S, Wasfy GH, Hedley DW, Minden MD, Penn cytarabine in older patients with untreated acute myeloid leukemia,

LZ. Lovastatin induces a pronounced differentiation response in acute excluding acute promyelocytic leukemia. Cancer 2008;113:2504–11.

myeloid leukemias. Leuk Lymphoma 2000;40:167–78. [140] Douer D, Watkins K, Louie R, Weitz I, Mohrbacher A, Levine AM.

[122] Burke LP, Kukoly CA. Statins induce lethal effects in acute myeloblas- Treatment of Non-APL acute myelogenous leukemia with intravenous

tic leukemia [corrected] cells within 72 hours. Leuk Lymphoma arsenic trioxide plus ascorbic acid. Blood 2006;108:554a.

2008;49:322–30.

[123] Lishner M, Bar-Sef A, Elis A, Fabian I. Effect of simvastatin

alone and in combination with cytosine arabinoside on the prolif-

eration of myeloid leukemia cell lines. J Investig Med 2001;49: Biographies

319–24.

[124] van der WK, de Jonge-Peeters SD, Kuipers F, de Vries EG, Vel-

lenga E. Combining simvastatin with the farnesyltransferase inhibitor

Antonio Rodriguez-Ariza, Ph.D., is a researcher at the

tipifarnib results in an enhanced cytotoxic effect in a subset of pri-

Maimonides Institute for the Biomedical Research, Cordoba,

mary CD34+ acute myeloid leukemia samples. Clin Cancer Res

2009;15:3076–83. Spain (IMIBIC). His research is focused on the role of impair-

[125] Kornblau SM, Banker DE, Stirewalt D, et al. Blockade of adaptive ment of cellular redox homeostasis on deregulated signaling

defensive changes in cholesterol uptake and synthesis in AML by in the pathogenesis of colon and breast cancer and hematopoi-

the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1

etic malignancies. Currently, he is involved in translational

study. Blood 2007;109:2999–3006.

projects for the development and implementation of new tar-

[126] Sassano A, Katsoulidis E, Antico G, et al. Suppressive effects

geted therapies in cancer.

of statins on acute promyelocytic leukemia cells. Cancer Res

2007;67:4524–32.

Chary López-Pedrera, Ph.D., is a researcher at the Mai-

[127] Tomiyama N, Matzno S, Kitada C, Nishiguchi E, Okamura N, Mat-

monides Institute for the Biomedical Research, Cordoba,

suyama K. The possibility of simvastatin as a chemotherapeutic

agent for all-trans retinoic acid-resistant promyelocytic leukemia. Spain (IMIBIC). Her main research issue on the area of hema-

Biol Pharm Bull 2008;31:369–74. tological malignancies has been focused on the study of the

256 A. Rodriguez-Ariza et al. / Critical Reviews in Oncology/Hematology 80 (2011) 241–256

molecular and cellular mechanisms involved in the regulation Nuria Barbarroja received her doctorate in 2006 at the

of angiogenesis and tumoral progression of acute myeloid Reina Soﬁa Hospital and University of Cordoba from Spain,

leukemia after treatment with newly developed antitumoral in the area of acute myeloid leukemia. She then obtained a

drugs. grant from the Jose Carreras International Leukemia Founda-

tion. She currently is a researcher at the IMABIS Foundation,

Enrique Aranda, M.D., Ph.D., is head of the Medical

Virgen de la Victoria Hospital, Málaga, Spain. Her scien-

Oncology Department of the University Hospital Reina Sofía,

tiﬁc work has been focused on the study of the intracellular

Cordoba, Spain. He is author of many articles in the ﬁeld

pathways that are related to the origin and pathogenesis of

of oncology, and has been involved in the development and

acute myeloid leukemia (AML). She has published several

effective implementation of new oncological therapies. At

papers in peer-review international journals in the Leukemia

the present time, he is engaged in both clinical and transla-

ﬁeld and other diseases where VEGF plays a relevant

tional research projects in the Maimonides Institute for the

role.

Biomedical Research, Cordoba, Spain (IMIBIC).