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Page 12 of 17 Testa et al. J Cancer Metastasis Treat 2020;6:53 I http://dx.doi.org/10.20517/2394-4722.2020.111
[81]
sensitized AML cells to chemotherapy . These observations suggest the potential use of VEGF-R2
inhibitors in association with antileukemia chemotherapy.

Other recent studies have explored the effects of apatinib, a new VEGF-R2 inhibitor. Apatinib is an oral
small-molecule tyrosine kinase inhibitor of VEGF-R2, showing in various experimental systems a marked
[82]
inhibitory activity on angiogenesis. This inhibitor showed promising effects in several solid tumors . In
vitro studies have shown that apatinib exerts a consistent cytotoxicity toward AML by targeting VEGF-
R2-mediated prosurvival signaling and angiogenetic effects. The sensitivity of AML blasts to apatinib was
correlated with some molecular features, including presence of Nucleophosphomin 1 (NPM1) mutations
and FAB M2 and M5 subtypes; importantly, AML blasts of relapsed/refractory patients displayed sensitivity
to apatinib [83,84] .

Sorafenib is a multi-kinase inhibitor exerting its effects by reducing the activity of various kinase receptors,
including VEGF-R2, Fms Like Tyrosine Kinase 3 (FLT3), and Kinase Insert Tyrosine kinase (KIT).
Sorafenib when used in monotherapy failed to exert a pronounced antileukemic activity in AML patients
with refractory/relapsing disease . However, a phase II study in untreated AML patients (aged £ 60 years)
[85]
explored the antileukemic activity of sorafenib added to standard induction chemotherapy compared to
placebo: sorafenib induced a significant prolongation of both event-free survival (EFS) and relapse-free
[86]
survival (RFS) compared to placebo . In an exploratory subgroup analysis, it was observed that no EFS
prolongation was observed among AML patients with FLT3-ITD mutation, while AML patient FLT3-
[86]
WT had significantly improved EFS and RFS . This finding suggests that an anti-angiogenesis effect of
sorafenib through inhibition of VEGF-R and platelet-derived growth factor receptors (PDGF-R) could
[86]
mediate the effect of this drug on significant prolongation of EFS and RFS .
In addition to VEGF and its receptors, the endothelial growth factors angiopoietin1 (Ang1) and
angiopoietin2 (Ang2) and their receptors Tie1 and Tie2 are also important regulators of physiologic
[87]
and pathologic angiogenesis . Peculiar is the function of the constitutively expressed Ang1 that acts
as a stabilizer of blood vessels. In addition, Ang1 through the binding to Tie2 promotes endothelial cell
[88]
survival and endothelial barrier function . Ang2 acts as a context-dependent agonist or antagonist of the
Ang1-Tie2 signaling axis . Ang2 is expressed by endothelial cells. Its levels are increased by hypoxia and
[87]
[69]
proinflammatory signals, and they are also increased in many types of cancers . In several tumor models,
there is evidence that Ang2 protects stressed endothelial cells from apoptosis and limits the effects
[89]
[90]
induced by VEGF inhibition .
[91]
The Ang-Tie system was explored in AMLs. In an initial study, Watarai et al. showed that an AML subset,
characterized by the inappropriate expression of the lymphoid membrane marker CD7, displays expression
of Ang2, in association with an elevated expression of integrin-family adhesion molecules. The expression
[91]
of Tie2 in these CD7 AMLs was low .
+
Schliemann et al. explored Ang1, Ang2, and Tie2 expression in 64 adult patients with newly diagnosed
[92]
AML. They observed that: (1) expression of Ang2 was significantly higher in the bone marrow of AML
patients than in healthy controls; (2) the expression of Ang1 in AML was similar to that observed in
normal controls; and (3) Tie2 expression was often increased in AML samples compared to the levels
[92]
observed in normal bone marrow . Ang2 levels but not Ang1 or Tie2 levels had a prognostic impact:
patients with high Ang2 levels exhibited a better overall survival compared to those with low Ang2
[92]
levels . In a subsequent study, the same investigators analyzed the prognostic impact of plasmatic Ang1,
[93]
Ang2, and soluble Tie2 (sTie2) in 68 AML patients . Circulating levels of Ang2 and sTie2, but not of
Ang1, were significantly elevated in AML patients as compared to controls . Higher levels of Ang2 and
[75]
sTie2 were predictive of poor survival in these patients; particularly, patients with elevated plasmatic Ang2