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| From OncoLog, June 2012, Vol. 57, No. 6 |
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VEGF Inhibitors: Promise and Challenges
By Stephanie Deming
All
of the antiangiogenic agents approved by the U.S. Food and Drug
Administration for cancer treatment primarily target vascular
endothelial growth factor (VEGF), a powerful regulator of the
development and function of blood vessels in tumors.
Since VEGF’s discovery nearly 30 years ago, basic science and clinical
researchers have been studying how blocking VEGF might slow or stop the
growth of tumors, which require a blood supply to survive and expand.
Lee Ellis, M.D., a professor in the Departments of Surgical Oncology
and Cancer Biology, ad interim chair of the Department of Cancer
Biology, and director of the Metastasis Research Center at The
University of Texas MD Anderson Cancer Center, began conducting
research in the field of antiangiogenic therapy in 1992. Since then, he
has seen tremendous initial excitement about antiangiogenic agents give
way to measured optimism, or even cynicism, based on clinical trial
results. “The improvement in patient outcomes with these drugs is
variable,” he said, “but it is less than we had anticipated.”
In 2003, the first phase III clinical trial of a VEGF inhibitor,
bevacizumab, showed that the agent’s addition to standard chemotherapy
for metastatic colorectal cancer increased overall survival by an
average of 4 months. To date, it is estimated that more than 30 VEGF
inhibitors have been identified and tested in more than 2,000 clinical
trials.
Today, five VEGF inhibitors are approved by the U.S. Food and Drug
Administration for cancer treatment: bevacizumab for non–small cell
lung cancer, recurrent glioblastoma, metastatic colorectal cancer, and
metastatic renal cell carcinoma (RCC); sunitinib for advanced RCC and
advanced pancreatic neuroendocrine tumors; pazopanib for advanced RCC
and advanced soft tissue sarcoma; axitinib for advanced RCC; and
sorafenib for advanced RCC and unresectable hepatocellular carcinoma.
Bevacizumab, probably the best-known VEGF inhibitor, is a monoclonal
antibody that binds to VEGF and thereby prevents VEGF from binding to
VEGF receptors. It is given intravenously once every 2–3 weeks.
Pazopanib, axitinib, sunitinib, and sorafenib are tyrosine kinase
inhibitors that block VEGF-induced cellular signaling. These drugs are
taken orally, typically once or twice a day.
Reviewing the current knowledge of VEGF inhibitor therapy, Dr. Ellis
said that one of the most important findings to date is that in most
types of cancer, including those of the colon, breast, and lung, VEGF
inhibitors confer no benefit unless they are administered in
combination with chemotherapy. Another important finding is that VEGF
inhibitors produce side effects such as hypertension and, rarely,
bleeding problems and blood clots.
“I think we’ve kind of hit a ceiling in designing new VEGF inhibitors,”
Dr. Ellis said. “There are only two ways to improve VEGF inhibitor
therapy: one is to find predictive biomarkers that indicate which
patients are going to respond and which are not, and the other is to
figure out how best to use VEGF inhibitors in combination with other
therapies. Identifying which patients are most likely to respond is
important because we do not want to administer a drug to a patient if
we know it will not be effective.”
Researchers are looking for biomarkers that could be measured to
identify likely responders before treatment. At the European Society of
Medical Oncology meeting in October 2011, researchers revealed evidence
that circulating levels of a form of VEGF-A predicted response to
bevacizumab in patients with glioblastoma. However, it is not clear
precisely what level of VEGF-A should be used as the cut-off to
distinguish which patients are likely to benefit. Furthermore, these
results came from a retrospective study and need to be validated
prospectively.
The search for other predictive biomarkers is made difficult by the
fact that the mechanisms of action of VEGF inhibitors remain unclear.
“It’s likely that the mechanisms of action are dependent on the
specific tumor type,” Dr. Ellis said. A number of theories have been
proposed to explain how these drugs work, including that the drugs
inhibit angiogenesis, inhibit vasculogenesis, normalize the tumor
vasculature, constrict blood vessels, alter the stem cell niche, or
exert immunologic effects. In any case, inhibition of angiogenesis
(i.e., blocking the proliferation of endothelial cells, which form
blood vessels) does not appear to be the sole explanation for the
drugs’ effects.
Dr. Ellis believes that VEGF inhibitors should continue to be tested in
combination with various types of drugs, including other antiangiogenic
therapies, signaling inhibitors, and chemotherapy drugs.
“We have to keep an open mind, but we shouldn’t use a shotgun
approach,” said Dr. Ellis, who is currently studying the role of VEGF
receptors on colon cancer cells. “We should take a very measured and
scientific approach based on validated, preclinical data that support
clinical trial development.”
For more
information,
contact the Office of Physician Relations at 713-792-2202.
Other
articles in OncoLog, June 2012 issue:
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