| originally
posted January 1, 2000
ANN ARBOR, MI
- By depriving cancer tumors of the copper supply they need
to form new blood vessels, researchers at the University of
Michigan report they have stopped the growth and spread of
the disease in a small group of advanced patients for more
than a year.
Five of six patients whose copper levels were
kept at one-fifth of normal for more than 90 days had no growth
of existing tumors or formation of new ones, according to
a paper published in the January, 2000 issue of Clinical
Cancer Research. The sixth had progression of only
one tumor; all others within her body remained stable. Twelve
other patients did not achieve the target copper level, or
could not stay at the target level for 90 days, because of
disease progression.
The surprising finding is the first evidence
in humans that physicians might fight multiple types of cancer
by targeting copper as a ‘common denominator’ of angiogenesis,
the process by which tumors grow the blood vessels that allow
them to expand beyond a tiny cluster of cells.
The copper strategy is not limited to a single
type of cancer, as are other anti-angiogenesis agents now
being studied around the world. Patients in the phase I trial
at the U-M had metastatic cancer of the breast, kidney, colon,
lung, skin, pancreas, prostate, throat, cartilage, blood vessels
or endothelium. All had exhausted other conventional treatment
options.
The U-M trial used oral doses of an inexpensive
compound called tetrathiomolybdate, or TM, to lower the patients’
copper levels. TM was originally developed for clinical use
by U-M Human Genetics Professor George J. Brewer, M.D., to
treat people with Wilson’s disease, a rare genetic disorder
caused by excess copper. His work has shown TM to be the world’s
most potent anti-copper agent, and has also demonstrated that
it is safe to use.
Aware of earlier research indicating that copper
is important for angiogenesis, Brewer did work in the early
90’s on animal cancer models treated with TM, with encouraging
results. Then, he teamed up with Sofia Merajver, Ph.D., M.D.,
a molecular genetics researcher and oncologist at the U-M
Comprehensive Cancer Center.
Independently, Merajver was interested in exploiting
the inhibition of angiogenesis at very early stages in cancer
development. Together with Brewer, she designed specific animal
studies that allowed the team to test whether TM had the ability
to prevent tumors from arising in animals at high-risk for
cancer. Her laboratory has also begun to elucidate the molecular
and cellular events involved in the inhibition of blood vessel
growth by copper deficiency.
Their first results from humans actually come
from a trial that was designed only to see how well TM could
reduce copper levels in cancer patients, not to test its effect
on the cancer itself. At all three daily dose levels given
in the trial, copper levels were reduced to 20 percent of
normal in four to six weeks. Neither the drug nor the long-term
copper deficiency produced side effects.
"What began as a scientific hunch now appears
to have potential as a simple but effective general anti-angiogenesis
strategy," says Brewer. "We are proceeding with
a clinical trial aimed at accelerating TM-induced copper reduction
and assess its effect on advanced-stage cancer. Later this
year, we hope to test this approach in 100 patients with five
types of less-advanced cancer." Neither trial is currently
accepting patients. For information on other clinical trials
visit our clinical
trial database.
Adds Merajver, "These initial results suggest
that the tactic of preventing angiogenesis through copper
deficiency holds significant promise. Through this and other
therapies, we may one day be able to turn cancer into a chronic
or controllable disease or to contribute to its eradication.
Still, much more research is needed before we can know the
full potential of anti-angiogenesis."
Angiogenesis happens in the body all the time,
whether to repair a wound or help with the normal growth of
children’s bodies. It occurs through a so-called angiogenesis
"cascade" — a series of biochemical steps by which
cells make and secrete molecules that initiate the growth
of capillaries. After the job is done, other molecular "factors"
turn off the angiogenesis process.
But cancer cells use this normal process for
a nefarious purpose, creating an imbalance of angiogenesis
activators that overrides the inhibitors and gives the nearby
tumor ready access to a blood supply. This creates a vicious
cycle of growth that allows tumors to grow faster than the
body can respond.
In recent years, researchers have found that
copper is a common denominator to several of the key factors
that activate the angiogenesis process. Specifically, it acts
as a co-factor to molecules known as basic fibroblast growth
factor (bFGF), vascular endothelial growth factor (VEGF) and
angiogenin. Without it, they can’t function; construction
of new blood vessels stops.
That’s why TM makes such a good choice, Brewer
explains. It binds with copper and protein, making a stable
compound that can’t be used by tumor cells or any other part
of the body. Taken at mealtime, TM prevents the body from
processing and absorbing the copper in food and the copper
normally found in saliva and gastric secretions. Taken between
meals, TM is absorbed into the blood and binds copper to blood
protein. In either case, the TM-protein-copper complex does
not interact with other biological molecules and is excreted.
The power of TM to stop angiogenesis in cancer
cells was clearly shown in an animal trial conducted by Brewer
and Merajver in mice specially bred to have a 100 percent
risk of breast cancer. The compound prevented cancer tumors
from growing in all the mice, a remarkable achievement that
encouraged the researchers to pursue the human trial. Animal
research elsewhere using another copper-reducing agent was
not as successful.
As reported in Clinical Cancer Research,
the trial found that 120 milligrams of TM per day was the
most effective dose of the three doses tested, bringing copper
levels to the target of 20 percent of baseline without side
effects. Brewer and Merajver call this level a "window"
that allows the body’s other copper-based reactions, such
as red blood cell function, to proceed but starves tumors
of the copper needed for angiogenesis. Patients who stop taking
TM have normal copper levels again within days.
Of the six patients who reached the target copper
level and remained on TM for more than 90 days, four are still
alive after treatment periods ranging from 11 months to 21
months. Two others have left the study but are still alive
after 6 and 17 months, respectively.
While not all patients in the U-M trial reached
the 20 percent target within the 90-day period specified,
the researchers believe that increased doses of TM will achieve
this goal in future patients. Already, the first two patients
in the new phase I/II trial have seen their cancer remain
stable after more than five months of treatment.
"We also believe that the earlier TM is
given in the progression of a patient’s cancer, the better
it should work," says Merajver. So, a 100-patient phase
II trial of TM in patients who have recently completed conventional
therapy for breast, prostate and kidney cancer, sarcoma and
multiple myeloma is being planned for this year.
A full-scale toxicity test of TM will also begin
shortly, though the compound has shown no toxic effects in
dozens of Wilson’s disease patients who have taken it to remove
copper from their bodies. Toxicity data are required before
TM can enter phase III clinical trials.
The U-M has filed for a new-use patent for TM
in the treatment of cancer and other diseases that rely on
angiogenesis. The University is currently in negotiations
with a pharmaceutical company to fund further research, part
of which will be directed at testing the efficacy of new compounds
with similar copper-lowering effects.
The research to date was funded by Food and
Drug Administration grants, gifts for Brewer’s work on TM,
National Institutes of Health grants for Merajver’s basic
research on mechanisms of copper-related angiogenesis, and
donations to the U-M Comprehensive Cancer Center.
The discovery of TM’s potential effect on cancer
grew directly out of Brewer’s decades-long research effort
on trace metals’ importance to the body. He began by examining
the role of zinc in sickle-cell anemia, a disorder of the
red blood cells, and unexpectedly found that zinc acetate
reduced the level of copper in the blood of some patients.
This gave him the idea to test the compound’s
effect on the dangerously high copper levels in the systems
of patients with Wilson’s disease, a potentially fatal recessive
genetic condition that strikes 5,000 teenagers and young adults
each year. Finding that zinc acetate brought the patients’
dementia, drooling, slurred speech, temper outbursts and tremors
under control if taken regularly, without side effects, he
sought and received FDA approval for the compound.
But he needed a faster-acting compound to bring
copper levels under control quickly. That compound turned
out to be TM, now in clinical trials at the U-M General Clinical
Research Center. To date, 63 Wilson’s disease patients have
come to the U-M for eight weeks of treatment with TM to lower
their copper levels, then returned home to take zinc acetate
and follow a copper-restricted diet to maintain their copper
levels.
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