Volume 1, Number 1
Release date: October, 2007 - Expiration date: October 2008
Estimated time to complete activity: 1.5 hours
Educational credits: 1.4 contact hours
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Angiogenesis, or the formation of new blood vessels, plays a central
role in disease pathogenesis, including tumor growth. It controls
important endothelial cell activities, including migration, proliferation,
and tube formation (Jain, 2004). In addition, angiogenesis
regulates pericytes, which surround the endothelial cells and
provide tubule stability (Hori, Ohtsuki, Hosoya, Nakashima, &
Terasaki, 2004).
Angiogenesis is strictly controlled by a balance between endogenous
activators and inhibitors (Ferrara, 2002; Table). The dysregulation
of this balance may cause the vascularization of tumors, promoting
their growth and metastasis. Because a tumor cannot grow
beyond 2 mm in size without its own blood supply providing the
necessary nutrients, the angiogenic shift, whereby the effect of the
endogenous activators outweighs that of the inhibitors, is critical to
tumor progression (Carmeliet & Jain, 2000).
Angiogenesis produces markedly different vasculature in tumor
tissue compared to healthy tissue. Whereas normal blood vessels
are typically highly ordered with an abundance of supporting pericytes,
the vasculature within a tumor is extremely disorganized and
twisted, and has a paucity of pericytes, leading to highly permeable
vessels (Figure 1; Ferrara, 2002).
Permeability is a hallmark of tumor vasculature and is often promoted
by one of the most potent angiogenesis activators, vascular
endothelial growth factor (VEGF). In addition to permeability,
VEGF promotes multiple cellular processes that are critical to
angiogenesis, including endothelial cell proliferation, survival, and
migration (Figure 2; Ferrara, 2002). Hypoxia is known to stimulate
upstream activators of angiogenesis, such as the transcription factor
hypoxia-inducible factor-1, which induces VEGF expression.
Other activators of angiogenesis include oncogenes, inflammatory
cytokines, and growth factors such as basic fibroblast growth factor
(bFGF) and platelet-derived growth factor (PDGF). PDGF functions
as a ligand or a family of PDGF receptors and is produced in
normal stromal cells (Adjei, 2005). Through binding to PDGF
receptors, PDGF regulates proliferation and migration.
An entirely new therapeutic class of drugs called targeted agents has
emerged over the past decade. Although their mechanisms of action
can be quite diverse, all drugs in this class specifically target one or a
limited number of cellular components, thereby selectively attacking
those cells containing the target (i.e., tumor cells) while sparing all others.
Because of this selectivity, targeted agents tend to have fewer
associated toxicities than traditional chemotherapy, although they do
have their own unique set of side effects, which may include dermatological,
cardiovascular, and gastrointestinal disturbances.
Ideally, a targeted agent will possess several characteristics. Most
important is its ability to target a component that is present on the
tumor cells, but absent on nontumor host cells. It is also desirable for
the drug to target an essential component of a key tumor process, such
as survival, proliferation, metastasis, or angiogenesis.
Angiogenesis occurs via several signal transduction pathways,
each of which is composed of ligands, transmembrane receptors,
and numerous cytoplasmic signaling intermediates. Signal transduction
refers to communication processes used by regulatory molecules
to affect various cellular processes, including cell growth,
proliferation, and survival. When signaling is disrupted or dysfunctional,
aberrations may lead to increased cellular proliferation (e.g.,
in tumor cells), sustained angiogenesis, invasion of normal tissues
by tumor cells, metastatic spread, and inhibition of apoptosis. Each
component of the signaling pathway is a potential target (Figures 3
and 4). Antiangiogenic agents are typically classified by their structure,
which in turn dictates the type of molecule that can be targeted.
The two main types of agents are monoclonal antibodies and tyrosine
kinase inhibitors (TKIs). Monoclonal antibodies, which are
extracellular proteins, have been developed to inhibit extracellular
ligands or receptors. Monoclonal antibodies competitively bind to
either ligands or receptors, which prevents ligand receptor binding
and disrupts subsequent signal transduction. TKIs are small molecules
that function intracellularly by binding to the tyrosine kinase
domain of a protein (either a transmembrane receptor or a signaling
intermediate), thereby blocking its enzymatic function and disrupting
the signaling pathway.
Targeting the VEGF pathway
The VEGF pathway has an essential role in angiogenesis and is
the most well characterized angiogenic pathway. Accordingly, the
VEGF pathway has been targeted by a number of existing antiangiogenic
drugs. Bevacizumab is a monoclonal antibody currently
approved for first- and second-line treatment of metastatic colorectal
cancer in combination with 5-fluorouracil–based chemotherapy and
for non-small cell lung cancer in combination with chemotherapy
(Avastin® prescribing information, 2006). Bevacizumab inhibits the
VEGF/VEGF receptor (VEGFR) interaction by binding to the
VEGF ligand, hampering the angiogenic process. As a humanized
antibody, bevacizumab is 93% human and 7% murine (Figure 5).
The first therapeutic monoclonal antibodies were developed in the
mouse and were therefore 100% murine. Unfortunately, these can
be highly immunogenic when administered to humans, producing
reactions ranging from an allergic rash to anaphylaxis. To reduce
these unwanted reactions, chimeric antibodies were developed in
which portions of murine antibodies and human antibodies were
fused together. Humanized antibodies are even less immunogenic
because a greater percentage of the antibody is derived from humans. Fully human antibodies are completely of human origin
and have no immunogenicity when administered to patients.
Targeting receptor tyrosine kinases
In addition to VEGF, other pathways important for angiogenesis
signal through receptor tyrosine kinases (RTKs). The RTK is composed
of three regions: an extracellular region input layer that binds
to the ligand, which could be a variety of growth factors, cytokines,
or other proteins; a transmembrane region that processes the cell
signaling; and an intracellular output region that serves to activate
the tyrosine kinase domain (Cohen, Cohen, & Meropol, 2005).
When the ligand binds to the receptor, generating receptor dimerization,
a signal is transmitted to activate the tyrosine kinase region.
This signaling is communicated from the receptor to the nucleus
where the actual cellular processing takes place, potentially resulting
in several outcomes, including cell growth, apoptosis, angiogenesis,
or metastasis. By inhibiting the tyrosine kinase activation, these
cellular processes are likewise blocked.
The epidermal growth factor receptor (EGFR) is one RTK that
represents considerable potential as a target for anticancer agents.
EGFR activation leads to important cellular processes such as
tumor cell proliferation, metastasis, and antiapoptosis (Pal &
Pegram, 2005). Expression of EGFR on many solid tumors has been
associated with similar processes that promote tumor growth and
spread. Two different mechanisms have been explored for tyrosine
kinase inhibition: monoclonal antibodies that focus on the extracellular
region and bind to the receptors and small-molecule TKIs that
act intracellularly.
Similar to bevacizumab, the TKI vatalanib can block the VEGF/
VEGFR interaction. Vatalanib accomplishes this through the intracellular
inhibition of the VEGFR kinase domain. In addition, the
agent binds to and inhibits the kinase domain of the PDGF receptor
(PDGFR), part of another angiogenic pathway. Vatalanib is currently
under investigation for the treatment of colorectal cancer in phase
III trials.
Two antiangiogenic TKIs that were approved by the FDA in 2006
are sunitinib and sorafenib. These TKIs have multiple targets and
are thus referred to as multitargeted agents. Both of these TKIs bind to and inhibit the VEGF, PDGF, FLT3 (FMS-like tyrosine kinase 3),
and KIT receptors; sorafenib further inhibits Raf kinase, an intracellular
signaling intermediate. These agents are both approved for use
in renal cell carcinoma, and sunitinib has an additional indication
for the treatment of gastrointestinal stromal tumor.
Because angiogenesis plays such a key role in tumor growth,
profileration, invasion, and metastasis, it has been the focus of
extensive cancer research. The complexity of the angiogenic
process engenders numerous targets that antiangiogenic agents may
exploit, including oncogenes, inflammatory cytokines, and growth
factors. Targets in the VEGF and TKR pathways are the focus of
ongoing investigational efforts and informed oncology nurses
should understand the role these targets play in the tumor biology
as well as how available treatments such as monoclonal antibodies
and TKIs work to exploit them.
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