San Diego, CA (5/6/98)- Researchers have been working
for decades to develop treatments for cancer based on blocking tumor blood
supply. Now a series of animal and clinical studies suggest this work is
starting to pay off.
The creation of new blood vessels, known as angiogenesis, is an essential
component of embryonic development, menstruation and wound repair.
It is also a critical element in tumor formation and growth. Cancer cells
secrete a number of angiogenesis factors encouraging new blood vessels
to sprout, providing essential nutrients for a tumor to grow.
Left unchecked, cells inside the tumor will eventually enter the blood
stream through the same blood vessels that feed it, spreading around the
body in a process known as metastasis.
most well known researcher in the angiogenesis field is Dr. Judah Folkman.
He has been working at Harvard University for 30 years to unlock the secrets
of cancer and blood vessel formation. His research began with an investigation
of how thalidomide caused birth defects. He determined that the notorious
drug appeared to inhibit embryonic blood vessel formation. Reasoning that
this kind of agent might prove useful in the fight against cancer, he began
studying tumor growth.
His work led to the current excitement generated by the announcement
that two genetically engineered proteins, angiostatin and endostatin eliminated
tumors in mice. Researchers reported that the proteins eliminated forms
of colon, prostate, breast and brain cancers in the animal experiments.
Angiostatin is a naturally occurring protein believed to inhibit tumor
growth by blocking blood vessel formation. It is related to fibrinogen.
Endostatin also appears to block new blood vessel growth in tumors. blocking
the metastatic process.
The new proteins will have to be evaluated much more thoroughly before
they can be used in human studies. Many potential cancer treatments that
looked promising in animal studies have not panned out in the clinic. A
series of human studies will be required to first test the safety of the
new drugs, then the potential efficacy against cancer. This process will
take at least two years.
Clinical Studies Now Underway
A number of other immunotherapeutic approaches to cancer treatment
directed against biological elements of tumor growth and metastasis are
already in clinical trials. Early clinical data from some of these trials
were presented at the 11th International Conference on Monoclonal Antibodies
"Changes occur early on in the angiogenic process when tumors produce
angiogenic cytokines, so attacking something common to the endothelium
may offer a new strategy. If we can inhibit the ability of blood vessels
to invade tumor, we can eliminate the tumor's ability to access the blood
supply as well as perturb its ability to get tumor cells into the circulation,"
noted David Cheresh, MD, Scripps Research Institute, La Jolla, CA.
Cheresh, who has been involved for many years in the development of
anti-integrin antibodies to disrupt tumor angiogenesis, believes the alphaVbeta3
receptor, part of the integrin family, should offer a good target for antiangiogenic
Cheresh and colleagues at the Sidney Kimmel Cancer Center recently completed
a clinical trial of a humanized antibody targeting the alphaVbeta3 integrin
receptor. Fifteen patients with late stage, progressive metastatic cancer
were treated with the antibody once week for six weeks. Preliminary results
showed no toxicity or serious side effects and some patients did respond
to the treatment.
"The early results indicate that the antibody treatment is safe and
possibly effective when given to right patients. Moreover, we've shown
it can be given on a prolonged basis, which is an important consideration
with the antiangiogenic approach. As opposed to an anticancer approach,
the antiangiogenic approach would have to be administered over a long period
of time," said Cheresh.
A number of researchers are working on antiangiogenesis approaches that
involve inhibition of vascular endothelial growth factor or VEGF.
Many human tumors overexpress VEGF mRNA, including those involving the
CNS, urinary tract, ovaries and endometrium. Animal studies have confirmed
that anti-VEGF antibodies do indeed inhibit tumor vascularity and growth.
These observations led to the development of a chimeric humanized antibody
targeting VEGF. Clinical studies are now in progress with the anti-VEGF
antibody alone and in conjunction with standard chemotherapy regimens
"The early results look promising, with significant reductions in tumor
size, and few side effects. Neovascularization is an essential piece in
tumorogenic cascade. The idea of blocking angiogenesis has broad application
across tumor types. I believe this kind of agent will lend itself to a
complementary treatment approach where we might attack the tumor with chemotherapy,
and the vasculature with the antibody," said Gwen Fyfe, MD, a researcher
Researchers are also evaluating another monoclonal antibody that targets
C225, another receptor associated angiogenesis. In animal studies the C225
antibody decreased tumor growth and increased survival in mice with
renal cell carcinoma. This agent is now being tested in humans, and has
been given as a single agent as well as in combination with various chemotherapy
regimens, in combination with radiation and as a single agent therapy following
These studies reflect a growing consensus among cancer researchers that
the new generation of immunotherapeutic anti-cancer agents will not replace
current treatments, but rather will complement and enhance them.