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Please note: This article is part of the Cancer Center's News Archive and is here for historical
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Sofia Merajver, M.D., Ph.D.,
Assistant Professor of Internal Medicine
Director, Breast and Ovarian Risk Evaluation Program
It has been more than 25 years since the initial insight put
forth by Dr. Judah Folkman that tumors require new blood vessel
growth (angiogenesis) to grow beyond very small lesions (under
1/4 inch). The field of angiogenesis concerns itself with
the study not only of tumor-associated vessels but with the
origin and remodeling of vessels during development, pregnancy,
ovulation, wound repair and processes that require tissue
regeneration. Breast cancer provided an important early clinical
insight into the workings of angiogenesis. Breast cancer clinicians
have recognized that the ability of breast cancer to recur
even many years after the original diagnosis and surgery may
be due to awakening of the angiogenic capabilities of "dormant"
cancer cells. These investigations have led to an increasingly
detailed understanding of the molecules and structures involved
in angiogenesis. The picture that has emerged is one of a
balance between molecules that promote and molecules that
impair angiogenesis. As tumors grow and their nutritional
needs increase, new blood vessels arise as a consequence of
an imbalance between stimulators and inhibitors of angiogenesis.
This work is leading to the rapid development of new cancer
therapies that address ways to diminish the action of the
stimulators of angiogenesis and promote the work of the inhibitors.
Anti-Angiogenesis Therapies
Important substances that impair angiogenesis have been isolated
from patients with cancer. Among several examples, angiostatin
and endostatin appear to hold promise in anti-tumor therapy.
However, these protein drugs are not yet in clinical trials.
Their ultimate usefulness in controlling cancer growth still
remains unproven, but expectations of success are cautiously
high, based on encouraging animal and other laboratory data.
Other avenues of investigation concern the use of antibodies
that prevent the action of angiogenesis stimulators by binding
to molecules on the surface of blood vessel cells. In this
way, these antibodies can block the binding of the stimulators
of angiogenesis. One important example in this category is
the antibody directed against the receptor for vascular endothelial
growth factor (known as anti-VEGF), which is already in clinical
trials. Anti-VEGF has been shown to slow down the growth of
tumors in several patients, with tolerable side effects. Interestingly,
anti-VEGF appears to also help the anti-tumor action of radiotherapy
when both modalities are used together. This "cooperation"
between treatment modalities is especially hopeful, since
it is expected that anti-angiogenesis therapies will be, in
general, well tolerated, and thus amenable to combinations
with other treatments.
The Role of Copper in Angiogenesis
At the University of Michigan Cancer Center, we have been
studying another approach to reducing new blood vessel growth
by impairing the action of angiogenesis stimulators. Many
studies in model systems have shown that key promoters of
angiogenesis require binding to copper in order to function
properly. This need for copper is fairly widespread among
pro-angiogenic molecules and has been observed to be present
in many different types of tumors.
Working together with Dr. George J. Brewer, an expert on the
metabolism of trace elements such as copper, we have developed
a clinical approach to exploiting the requirement of copper
for angiogenesis. Drugs that lower copper levels exist in
clinical practice primarily for the purpose of treating a
rare hereditary disorder known as Wilson's disease. Patients
with this condition do not have the ability to transport copper
normally, and thus it accumulates in great quantities in organs
such as liver and brain, causing severe malfunction often
leading to death. However, with appropriate copper-lowering
therapy, Dr. Brewer and others have developed well-tolerated
therapies to control the level of copper in patients with
Wilson's disease with excellent results. A particularly potent
drug to lower copper in the body is the small molecule tetrathiomolybdate
(TM) which is safely administered to patients with Wilson's
disease.
U-M Clinical Trial with Tetrathiomolybdate (TM)
After completing an animal study that showed that TM was extremely
effective in preventing the development of overt mammary tumors
in cancer-prone mice, we embarked on a Phase I trial of TM
in humans with metastatic cancer. After a year, this trial
has now completed accrual. The patients in the trial have
tolerated TM extremely well, with nearly no side effects.
It is important to remember that copper is required for many
cellular processes, and in fact, absence of copper or very
low copper levels would be very harmful to patients. The key
observation of our trial is that it is possible to inhibit
angiogenesis in many tumor types by lowering the copper to
levels that still allow most other cellular processes to proceed
relatively undisturbed. In this way, if patients can remain
within a well-defined but apparently not too narrow "window"
of mild copper deficiency, angiogenesis is brought to a halt
without any other major side effects. It is important to point
out that copper levels can be easily restored to normal in
a matter of hours to days, by simply ceasing administration
of TM.
Whereas new blood vessels appear to have a very strong dependence
on copper for growth, low copper levels are unlikely to affect
existing vessels; however, as tissue turnover eventually occurs,
"old" vessels will not be replaced by new vessels, in the
setting of copper deficiency. Therefore we postulated that
in patients with established tumors, the achievement of chronic
disease, and perhaps a very slow decrease in the number of
viable tumor cells would be observed in cases in which TM
is successful.
In addition, we have observed encouraging hints of cooperativity
between TM and Herceptin(r) (anti-HER2 antibody) in breast
cancer; TM and radiotherapy in kidney cancer; and TM and interferon
in angiosarcoma. We are planning new trials to specifically
study the efficacy of TM alone and in combination with other
approaches in controlling metastatic sarcoma, breast and kidney
cancer, and earlier stages of cancer. Although the results
are promising, the exact clinical uses of this approach are
yet to be rigorously defined in clinical trials.
Summary
Angiogenesis holds significant promise to help render cancer
into a chronic or controllable disease or to contribute to
its eradication, most likely in combination with other therapeutic
modalities. The work in this field constitutes one more example
of the concept that knowledge of the molecular and cellular
events involved in cancer will lead to new therapies.
Additional References
Irani JL, van Golen K, Lovelace JR, Brewer GJ, Merajver SD.
Copper deletion as an anti-angiogenic strategy in HER2-neu
transgenic mice. Abstract presented at the AACR's Special
Conference, "Angiogenesis and Cancer." 1998.
Hanahan D, Folkman J. Patterns and emerging mechanisms of
the angiogenic switch during tumorigenesis. Cell. 86:353-364,
1996.
Folkman J. The influence of angiogenesis research on management
of patients with breast cancer. Breast Cancer Res Treat. 36:109-118,
1995.
Folkman J. Angiogenesis inhibitors generated by tumors. Mol
Med. 1:120-122, 1995.
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