H e m a t o lo g y E d u c a t io n - European Hematology Association

16 th Congress of the European Hematology Association
relapsed/refractory patients, including complete response
or near complete response in 21%. This regimen produced
responses in 98–100% of newly-diagnosed MM patients. 55
Recently, we have demonstrated that lenalidomide, at
clinically achievable concentration, is antiangiogenic in
vivo and inhibits MMECs migration. 47 Lenalinomide
halts the MMECs’ overangiogenic potential by downregulating
key angiogenic genes and VEGF/VEGFR-2mediated
downstream signaling pathways involved in
cell motility, and NF-kB. A comparative proteomic
analysis reveals that lenalidomide-treated MMECs
modulate the expression levels of angiogenesis-related
genes controlling cell motility and invasiveness, cell
shape, and cytoskeletal dynamic remodeling, as well as
energy metabolism pathways and protein clearance. 47
Bortezomib
It is a proteasome inhibitor, which induces endothelial
cell apoptosis, 56 inhibits VEGF, IL-6, Ang-1 and Ang-
2, and IGF-1 secretion in BMSCs and endothelial cells
from MM patients, 57,58 HIF-1α activity, 59 downregulates
caveolin-1 tyrosine phosphorylation, which is required
for VEGF-mediated MM cell migration, and also blocks
the caveolin-1 phosphorylation induced by VEGF in
endothelial cells, thereby inhibiting ERK-dependent cell
proliferation. 60
Roccaro et al. demonstrated that bortezomib inhibits
the proliferation of MMECs in a dose- and time-dependent
manner. 57 Moreover, in endothelial cell functional
assays, including chemotaxis, adhesion to fibronectin,
capillary formation on Matrigel, and chorioallantoic membrane
(CAM) assay, bortezomib demonstrated a dosedependent
inhibition of angiogenesis. Bortezomib has
been previously approved for MM patients who failed at
least one prior therapy, 61 and for initial treatment in a pivotal,
multicenter, open-label trial, in which 682 previously
untreated patients, who were ineligible for high-dose
therapy plus stem-cell transplantation, were randomized
to receive melphalan and prednisone combination alone
(control group) or with bortezomib. 62 The time to progression
among patients receiving bortezomib plus melphalan/prednisone
was 24 months, as compared with 16.6
months among those receiving melphalan/prednisone
alone (control group). The overall survival and response
rates were also better in the bortezomib group. 62
The use of bortezomib in pre-transplant induction
therapy revealed a higher response rate, compared with
other induction regimens. 63 Recently, we demonstrated
that bortezomib and zoledronic acid display distinct
and synergistic activities on bone marrow macrophages
of MM patients. 64 Drugs inhibited macrophage proliferation,
adhesion, migration, and expression of angiogenic
cytokines and capillarogenesis on Matrigel.
Moreover, VEGFR-2 and ERK-1/2 phosphoactivation, as
well as NF-kB were also inhibited. Preclinical studies
with new proteasome inhibitors are underway. 65,66
Tyrosine kinase inhibitors in the treatment of MM
Receptor tyrosine kinases (RTKs) are transmembrane
proteins containing an extracellular lectin binding
domain and an intracellular catalytic domain. Many of
the processes involved in tumor growth, progression,
and metastasis are mediated by signaling molecules acting
downstream from activated RTKs. Tyrosine kinase
inhibitors (TKIs) are small molecules able to pass the
plasma membrane. 67 The tyrosine kinase VEGFRs are
crucial mediators in angiogenesis. Stimulation of
VEGFRs and other RTKs causes massive activation of
signaling pathways in endothelial cells. TKIs inhibit not
only VEGFRs but also other receptors in the super-family
of RTKs, including PDGFR. Inhibitors of VEGF signaling
not only interfere with angiogenesis but also
cause regression of some tumor vessels, 68 giving changes
in all components of the vessel wall, consisting in loss of
endothelial cell fenestrations, regression of tumor vessels,
and appearance of basement membrane ghosts. 69
In 2005, the FDA granted regular marketing approval
for sorafenib, a small oral inhibitor for the treatment of
patients with advanced renal cell carcinoma. 70 It is a small
oral multi-TKI of VEGFR, PDGFR, c-kit, and Flt-3 kinase
activity. 71 TKIs can be taken orally, if necessary in a salt
form of the inhibitor. For example, sunitinib is taken as
sunitinib malate, while sorafenib as tosylate sorafenib.
Lin et al. showed that vatalanib (PTK787/ZK222584), an
orally administered broad-spectrum TKI of VEGFR-1,-2,-
3, PDGFR-β, c-kit, inhibited proliferation and migration of
MM cells. 72 Pandiella et al. showed that imatinib mesylate
(STI571) blocked cell-cycle progression in MM and
potentiated the effects of conventional anti-MM agents in
vitro. 73 However, in a phase II trial in patients with refractory/relapsed
disease, no response was obtained. 74
Zangari et al. and Kovacs et al. evaluated the activity
of SU5416, a small TKI of VEGFR-1,-2,-3, and vandetanib
(ZD6474) in patients with refractory MM, and
observed a decrease in VEGF serum levels in patients
with stable disease, but not with objective response. 75,76
Podar et al. demonstrated that pazopanib (GW786034B)
and GW654652, two broad-spectrum TKIs of VEGFR-
1,-2,-3, PDGFR, c-kit, inhibited in vivo MM cell proliferation,
migration, and survival, VEGF-induced up-regulation
of adhesion molecules on both endothelial and
tumor cells, and exerted an antiangiogenic activity in
vivo. 77 However, a phase II trial in 21 MM patients treated
with pazopanib gave no appreciable response. 78
Ramakrishnan et al. showed that sorafenib exerted a
significant anti-MM activity and synergized with common
anti-MM drugs. 79 Coluccia et al. have shown constitutive
activation of PDGFR-β/Src, two dasatinib targets,
in plasma cells and MMECs. 22 Moreover, dasatinib
significantly delayed MM tumor growth and angiogenesis
in vivo, showing a synergistic cytotoxicity with
other anti-MM drugs, that is, melphalan, prednisone,
bortezomib, and thalidomide.
In about 10–20% of MM patients, a translocation
[t(4;14)] involving FGF receptor-3 (FGFR-3) is associated
with poor prognosis. 80–82 Small molecules with selective
TKI activity (SU5402, SU10991, PD173074, PKC412)
have been validated in preclinical models of MM. 83–85
Zoledronic acid ZOL
This is a bisphosphonate used for MM bone disease
and hypercalcemia. ZOL has a direct cytotoxic activity
on tumor cells and suppresses angiogenesis. 86,87 We have
demonstrated that therapeutic doses of ZOL markedly
inhibit in vitro proliferation, chemotaxis, and angiogenesis
of MMECs, and in vivo angiogenesis in the CAM. 88
These effects are partly sustained by gene and protein
inhibition of VEGF and VEGFR-2 in an autocrine loop.
| 276 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)