Angiogenesis is the formation of new blood vessels. Tumors need blood vessels to grow and spread.
Angiogenesis inhibitors are designed to prevent the formation
of new blood vessels, thereby stopping or slowing the growth or spread
of tumors.
The U.S. Food and Drug Administration has approved several angiogenesis inhibitors for the treatment of cancer.
Angiogenesis inhibitors may have side effects that are
different from those of other cancer treatments. In addition, they may
only stop or slow the growth of a cancer, not completely eradicate it.
What is angiogenesis?
Angiogenesis is the formation of new blood vessels. This process involves the migration, growth, and differentiation of endothelial cells, which line the inside wall of blood vessels.
The
process of angiogenesis is controlled by chemical signals in the body.
These signals can stimulate both the repair of damaged blood vessels and
the formation of new blood vessels. Other chemical signals, called
angiogenesis inhibitors, interfere with blood vessel formation.
Normally, the stimulating and inhibiting effects of these chemical
signals are balanced so that blood vessels form only when and where they
are needed.
Why is angiogenesis important in cancer?
Angiogenesis
plays a critical role in the growth and spread of cancer. A blood
supply is necessary for tumors to grow beyond a few millimeters in size.
Tumors can cause this blood supply to form by giving off chemical
signals that stimulate angiogenesis. Tumors can also stimulate nearby
normal cells to produce angiogenesis signaling molecules. The resulting
new blood vessels “feed” growing tumors with oxygen and nutrients, allowing the cancer cells to invade nearby tissue, to move throughout the body, and to form new colonies of cancer cells, called metastases.
Because
tumors cannot grow beyond a certain size or spread without a blood
supply, scientists are trying to find ways to block tumor angiogenesis.
They are studying natural and synthetic angiogenesis inhibitors, also
called antiangiogenic agents, with the idea that these molecules will prevent or slow the growth of cancer.
How do angiogenesis inhibitors work?
Angiogenesis
requires the binding of signaling molecules, such as vascular
endothelial growth factor (VEGF), to receptors on the surface of normal
endothelial cells. When VEGF and other endothelial growth factors bind
to their receptors on endothelial cells, signals within these cells are
initiated that promote the growth and survival of new blood vessels.
Angiogenesis inhibitors interfere with various steps in this process. For example, bevacizumab (Avastin®) is a monoclonal antibody that specifically recognizes and binds to VEGF (1).
When VEGF is attached to bevacizumab, it is unable to activate the VEGF
receptor. Other angiogenesis inhibitors, including sorafenib and
sunitinib, bind to receptors on the surface of endothelial cells or to
other proteins in the downstream signaling pathways, blocking their
activities (2).
Are any angiogenesis inhibitors currently being used to treat cancer in humans?
Yes. The U.S. Food and Drug Administration (FDA) has approved bevacizumab to be used alone for glioblastoma that has not improved with other treatments and to be used in combination with other drugs to treat metastatic colorectal cancer, some non-small cell lung cancers, and metastatic renal cell cancer.
Bevacizumab was the first angiogenesis inhibitor that was shown to slow
tumor growth and, more important, to extend the lives of patients with
some cancers.
The FDA has approved other drugs that have antiangiogenic activity, including sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), and everolimus (Afinitor®).
Sorafenib is approved for hepatocellular carcinoma and kidney cancer,
sunitinib and everolimus for both kidney cancer and neuroendocrine
tumors, and pazopanib for kidney cancer. Researchers are exploring the
use of angiogenesis inhibitors to treat other types of cancer (see
Question 7). In addition, angiogenesis inhibitors are being used to
treat some diseases that involve the development of abnormal blood
vessel growth in noncancer conditions, such as macular degeneration.
How are angiogenesis inhibitors different from conventional anticancer drugs?
Angiogenesis
inhibitors are unique cancer-fighting agents because they tend to
inhibit the growth of blood vessels rather than tumor cells. In some
cancers, angiogenesis inhibitors are most effective when combined with
additional therapies, especially chemotherapy. It has been hypothesized
that these drugs help normalize the blood vessels that supply the tumor,
facilitating the delivery of other anticancer agents, but this
possibility is still being investigated.
Angiogenesis inhibitor
therapy does not necessarily kill tumors but instead may prevent tumors
from growing. Therefore, this type of therapy may need to be
administered over a long period.
Do angiogenesis inhibitors have side effects?
Initially,
it was thought that angiogenesis inhibitors would have mild side
effects, but more recent studies have revealed the potential for
complications that reflect the importance of angiogenesis in many normal
body processes, such as wound
healing, heart and kidney function, fetal development, and
reproduction. Side effects of treatment with angiogenesis inhibitors can
include problems with bleeding, clots in the arteries (with resultant
stroke or heart attack), hypertension, and protein in the urine (3–5). Gastrointestinal perforation and fistulas
also appear to be rare side effects of some angiogenesis inhibitors.
Animal studies have revealed the potential for birth defects, although
there is no clinical evidence for such effects in humans.
It is
likely that some of the possible complications of angiogenesis inhibitor
therapy remain unknown. As more patients are treated with these agents,
doctors will learn more about possible rare side effects.
What is the ongoing research on angiogenesis inhibitors?
In
addition to the angiogenesis inhibitors that have already been approved
by the FDA, others that target VEGF or other angiogenesis pathways are
currently being tested in clinical trials
(research studies involving patients). If these angiogenesis inhibitors
prove to be both safe and effective in treating human cancer, they may
be approved by the FDA and made available for widespread use.
In addition, phase I and II
clinical trials are testing the possibility of combining angiogenesis
inhibitor therapy with other treatments that target blood vessels, such
as tumor-vascular disrupting agents, which damage existing tumor blood
vessels (6).
The list below includes cancers that are being studied in active phase III treatment clinical trials using angiogenesis inhibitors. The clinical trials can be found in NCI’s list of clinical trials. For information about how to search the list, see “Help Using the NCI Clinical Trials Search Form.”
