Download Post Office Will Issue Stamp to Benefit Breast Cancer Research

fall into a gray area that isn't really an
embargo break, but merely looks like one.
"It gets sticky if a reporter has been
following a study for some period of
time," Bor said. If the reporter has followed the preliminary work and is keeping tabs on the research, it is possible to
write the story ahead of the embargo
date without ever seeing an embargoed
copy of the research paper. Because the
reporter gathered the material for the
story on his own, he isn't breaking the
embargo, even if the effect is virtually
identical.
"You need to look at these things on
a case-by-case basis," Bor said. "It may
look like an embargo break, but it's just
good journalism."
According to Palca, embargoes can
be annoying or frustrating at times to
journalists, but he doesn't see them
disappearing soon. The trade offs are
ones all sides have grown accustomed
to. "We'll still have the embargo until
it's proven not to be feasible," Palca
said.
-Laurent Castellucci
Post Office Will Issue Stamp to Benefit
Breast Cancer Research
The U.S. Postal Service will issue in August the first U.S. postage stamp to
have its net proceeds from sales earmarked for research organizations. The stamp,
called a semipostal because of its use for more than postage, will cost 40 cents.
Seventy percent of the net proceeds from the stamp's sale will support breast
cancer research funded by the National Institutes of Health and 30% will support
breast cancer research supported by the Department of Defense, agencies that
were identified in the law that required the Postal Service to issue the stamp. The
legislation directed that the stamp be valid for first-class postage, now 32 cents,
and allowed the Postal Service to charge
up to 25% above the first-class rate torecover reasonable costs associated with the
stamp and to support research.
After the stamp is issued next month,
the Postal Service will join with breast
cancer organizations and other groups to
hold "awareness' events around the country for the stamp. The stamp's colorful
design contains the phrases: "Fund the
Fight" and "Find a Cure."
The stamp was designed by Ethel
Kessler ofBethesda, Md., and illustrated
by Whitney Sherman of Baltimore.
Kessler is a breast cancer survivor and is
working on other U.S. stamp designs. The
stamp can be viewed at the Postal
Service's web site (http://www. usps.gov/
fr_stamps.html).
960 NEWS
Inhibitors of
Angiogenesis Enter
Phase III Testing
Most cancer centers will not forget
May 3, 1998, and the week that followed. That Sunday marked the publication of a New York Times piece suggesting that two molecules, angiostatin and
endostatin, would cure cancer in 2 years.
During the crush of calls and intense
media coverage that followed, the public
learned that human trials were at least a
year away, awaiting production of large
quantities of the compounds and testing
in animals for toxicity.
What was largely overlooked in the
brouhaha was the fact that about 20
similar drugs, angiogenesis inhibitors,
have already begun testing in humans.
Three- Ag3340, Bay 12-9566, and
marimastat - are in phase III trials,
with results from the marimastat trial
expected as early as next year.
"At this point, however, it's impossible to say whether any of the angiogenesis inhibitors will work," said James
M. Pluda, M.D., senior clinical investigator of the Investigational Drug Branch
of the National Cancer Institute. "We
simply don't have the data. The trials
have not been completed."
Angiostatin and endostatin were
discovered in the laboratory of Judah
Folkman, M.D., at Harvard Medical
School and Children's Hospital in Boston. Over the last 30 years, Folkman has
amassed data showing that tumor growth
and metastasis are dependent on the
development of new blood vessels, a
process known as angiogenesis. Preventing blood vessel growth, he reasoned,
would prevent tumors from growing
beyond the size of a pinhead, at which
point most tumors are likely to be benign.
Journal of the National Cancer Institute, Vol. 90, No. 13, July I, 1998
Endothelial cells, the cells that line
blood vessels, are the source of new
blood vessels and have a remarkable
ability to divide and move. A new blood
vessel is created when an endothelial
cell from the wall of a small blood vessel attaches to the surrounding membrane (extracellular matrix), secretes
enzymes that degrade the membrane,
invades it, and begins dividing. Eventually strings of dividing cells are hollowed out to form tubes, creating new
networks of blood vessels that make
normal tissue growth and repair possible.
Most of the time endothelial cells lie
dormant. When needed, brief bursts of
blood vessel growth occur in localized
parts of tissues. New growth is tightly
controlled by a finely-tuned balance
between factors that stimulate endothelial cell growth and those that inhibit it.
About 15 proteins are known to
stimulate endothelial cell growth and
movement, including epidermal growth
factor, angiogenin, estrogen, fibroblast
growth factors
(acidic and
basic), and
vascular endothelial
growth factor
(VEGF).
Some ofthe
known inhibitors of angiogenesis include
Dr. James M. Pluda
angiostatin,
endostatin, platelet factor 4, interleukin
12, retinoic acid, and tissue inhibitors of
metalloproteinase-1 and -2 (TIMP-1 and
-2). Two endothelial growth factors,
VEGF and basic fibroblast growth factor
(bFGF), are expressed by many tumors
and seem to be important in sustaining
tumor growth.
Of the angiogenesis inhibitors in
clinical trials, most were designed to
target specific molecules involved in
new blood vessel formation. For others,
the exact mechanism of the drug is not
known, but it has been shown to inhibit
angiogenesis by specific laboratory tests
(in the test tube or in animals). (See box
on next page.)
Naturally Occurring Inhibitors
One treatment strategy is simply to
use the natural inhibitors of endothelial
cell division. Angiostatin and endostatin, small fragments oflarger more
familiar molecules, collagen and plasminogen, fall into this class of drug. "They
are probably part of a highly regulated
system of circulating activators and
inhibitors that the body uses to quickly
grow new vessels when needed," said
MichaelS. O'Reilly, M.D., of Children's Hospital in Boston, the discoverer of both compounds and a member
of Folkman's lab.
Although the animal studies are very
promising, both because the mouse
tumors disappear and the animals show
no drug resistance, human studies will
not begin for another year or more. Two
other natural inhibitors of angiogenesis,
platelet factor 4 and interleukin 12, are
also in early phase clinical trials.
Rather than focusing on inhibitors,
scientists at several C?mpanies have
taken a different tack- they are hoping
to block the factors that stimulate endothelial cell growth. Researchers at Genentech, Inc., in San Francisco, are testing
a monoclonal antibody against VEGF in
early trials. Scientists at Sugen, Inc., in
Redwood City, Calif., have synthesized a
small molecule that prevents VEGF from
binding to its epithelial cell receptor. They
are testing it in early trials.
Furthest along in development are
the drug compounds aimed at prevent-
Journal of the National Cancer Institute, Vol. 90, No. 13, July 1, 1998
ing new blood vessels from invading
surrounding tissue. These drugs are
inhibitors of the matrixmetalloproteinases (MMPs). MMPs are a family of
15 enzymes (called metallo because
all contain a zinc atom at their active
site) responsible for normal turnover
and remodeling of the extracellular
matrix, the membrane that holds cells
together inside tissues. MMPs are
capable of breaking down most components in the extracellular matrix,
including collagen, laminin, fibronectin, and elastin. Both angiogenesis
and metastasis require MMPs during
blood vessel and tumor invasion.
Because elevated levels of specific
MMPs have been reported in tumor
growth and metastasis, several companies have
synthesized
specific inhibitors of
various MMPs
as a strategy to
treat cancer.
A spokesperson from
Agouron Pharmaceuticals,
Inc., in La
Dr. Judah Folkman
Jolla, Calif.,
said they have just completed two phase
I trials with their inhibitor, Ag3340,
treating 71 patients with advanced tumors in one, and 15 with prostate cancer
in the other. The data, presented in
Amsterdam at the EORTC (European
Organization for Research and Treatment of Cancer) meeting in June, gave
them enough confidence to begin recruiting in May for phase II/III trials
with 500 prostate and 500 lung cancer
patients at 50 centers in North America.
Like Agouron, researchers at Bayer
Corporation in West Haven, Conn., have
synthesized an inhibitor of MMPs, Bay
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961
12-9566, that is specific for two enzymes highly expressed in cancers,
MMP-2 and MMP-9. Bayer has also
completed a phase I trial of its Bay
12-9566 with 90 patients and has begun recruiting 800 patients for phase
II/III trials.
Rachel W Humphrey, M.D., associate director of clinical oncology at
Bayer, said the drug was safe and extremely well tolerated, but that the effectiveness will have to be determined
by the randomized trials. "What we can
safely say at this point is that the patients were not getting sicker, quicker,"
she said.
The strategy of researchers at British Biotech Inc., in Annapolis, Md.,
was to synthesize an inhibitor, marimastat, that has a broad specificity for
many of the MMPs. The marimastat
phase III trials began 2.5 years ago.
Pancreatic, glioblastoma, and lung
cancer trials are furthest along and
trials in gastric, ovarian, and breast
cancers are not far behind. Each trial
has about 300 patients.
Henrik Rasmussen, Ph.D., senior
vice president of clinical research and
regulatory affairs at British Biotech,
predicts that results will be available
soon. "We'll have the results from the
first four phase III studies - pancreatic,
gastric, glioblastoma, small-celllungsome time in 1999."
Rasmussen said that marimastat is
less well tolerated than the Bayer inhibitor, which is to be expected from a compound that affects more enzymes. The
primary toxicity is to the joints and
muscles. However, he said that very few
patients drop out and that they can keep
patients on trials for long periods of
time. Patients who are affected are taken
off the drug, and when the symptoms
have subsided, treatment is re-started at
half the dose.
962
NEWS
Angiogenesis Inhibitors in Clinical Trials
Phase II and III Only
Drug
Sponsor
Trial
Mechanism
Drugs that prevent new blood vessels from invading surrounding tissue:
Marimastat
British Biotech
Annapolis, MD
Phase III
Bay 12-9566
Bayer
West Haven, CT
Phase III
Synthetic inhibitor of
matrixmetalloproteinases
(MMPs)
Synthetic MMP inhibitor
Ag3340
Agouron
La Jolla, CA
Phase III
Synthetic MMP inhibitor
Phase II
Inhibits endothelial
cell growth
Inhibits endothelial
growth
Natural inhibitors of angiogenesis:
Platelet factor-4
Interleukin 12
Rep ligen
Cambridge, MA
Genetics Institute
Cambridge, MA
Phase 1/II
Drugs that block factors that stimulate the formation of blood vessels:
RhuMad VEGF
Genentech
Phase II
San Francisco, CA
SU5416
Sugen, Inc.
Phase II
Redwood City, CA
Commercially
Phase IIII
available
Interferon-alpha
Monoclonal antibody to
vascular endothelial
growth factor (VEGF)
Molecule that blocks
VEGF receptor
Inhibits release of endothelial growth factor
Targeted anti-vascular therapy:
ZD0101
Zeneca
Pharmaceuticals
Wilmington, DE
Phase II
Bacterial toxin that binds
to new blood vessels and
induces inflammatory
response
Interrupts function of dividing endothelial cells:
TNP-470,
TAP Pharmaceuticals, Inc.
Deerfield, IL
Phase II
Synthetic analogue of
fungal protein - inhibits
endothelial cell growth
Unknown mechanism; inhibits angiogenesis in laboratory and animal assays:
Thalidomide
Entremed, Inc.
Rockville, MD
CAl
NCI
Phase IIII
Bethesda, MD
Park-Davis
Phase II/III
Morris Plains, NJ
Cytran
Phase II
Kirkland, WA
Suramin
IM862
Phase II
Synthetic sedative:
mechanism unknown
Non-specific inhibitor of
cell invasion and motility
Non-specific, multi-site
effects
Mechanism unknown
Journal of the National Cancer Institute, Vol. 90, No. 13, July 1, 1998
Neither marimastat nor Bayer's compound appear to affect wound healing.
Because angiogenesis is vital to cell
growth and wound healing, researchers
have been concerned about possible
side effects. So far, neither drug affected
patients who required surgery while they
were on the drug.
Perhaps reacting to the over-promise
of the May New York Times article, several company spokespersons were extremely reluctant to convey any optimism
about their products. But, in theory, there
may be several beneficial by-products
that result from the fact that angiogenesis
inhibitors target normal dividing endothelial cells, and not tumor cells. One is
that they are not likely to cause bone
marrow suppression, gastrointestinal
symptoms, or hair loss, characteristic of
standard chemotherapy. Also, drug resistance may not develop because endothelial cells are not genetically unstable.
Most cancer cells have a propensity for
mutation and genetic diversity, and are
therefore likely to produce drug-resistant
cells. None of the trials have lasted long
enough to evaluate resistance.
Also, because anti-angiogenic drugs
are designed to prevent the further
growth of tumors, but do not necessarily kill tumors, anti-angiogenic therapy
may prove useful in combination with
therapy aimed at tumor cells. Early
trials using marimastat and another
angiogenesis inhibitor, TNP-470, in
combination with standard cytotoxic
drugs have begun.
For some researchers, however, not
even cautious optimism seems appropriate. "All the information we have is that
the drug is working," said Rasmussen.
"We have treated 2,500 patients and we
haven't seen any problems yet. I would
be stunned if the drug doesn't work."
-NancyJ. Nelson
Colon Cancer: New Drug
Options Improve on 5-FU
For years, 5-fluorouracil- with or
without either oral leucovorin or levamisole- has been about the only chemotherapy option for colorectal cancer
patients. But recent insights into the
biology of this cancer have spurred
development of new drugs that researchers hope will not only work better but
carry less toxicity.
The prospect of these new experimental treatments, which are now available or expected to be
so shortly,
created jampacked sessions at two
cancer meetings earlier
this yearthe American
Society of
Clinical OnDr. Yousef Rustum
cology in Los
Angeles and the International Congress
on Anti-Cancer Treatment in Paris.
"People are clearly looking for a new
drug for a disease that is difficult to
treat," noted Yousef Rustum, Ph.D., a
senior vice president for scientific affairs at Roswell Park Cancer Institute in
Buffalo, N.Y., who chaired an ASCO
educational session on new drugs for
colon cancer.
Added Richard Pazdur, M.D., professor of medicine at the University of
Texas M. D. Anderson Cancer Center,
Houston, "In essence [with 5-FU], we
have a marginally active drug that has
significant toxicities when used in optimal fashion." Pazdur, who spoke both in
Journal of the National Cancer Institute, Vol. 90, No. 13, July I, 1998
Paris and Los Angeles, said that although 5-FU has been used in a variety
of ways, "fewer than a third of the patients achieve an objective response rate
with 5-FU and approximately 20% of
patients in large clinical trials are hospitalized for treatment-related toxicity."
A Full Menu
Among the three classes of drugs
under study, some of which are already
approved for use in the United States or
in other countries, are the folate-based
thymidylate synthase (TS) inhibitors,
such as raltitrexed (Tomudex); the oral
fluorinated pyrimidines, such as the
recently approved (for a breast cancer
indication) capecitabine; and the topoisomerase I inhibitors, such as topotecan
or CPT-11 (irinotecan), which was recently approved by the Food and Drug
Administration for refractory breast
cancer and has now shown promise in
the treatment of colorectal cancer. In
addition, researchers are evaluating a
platinum compound, oxaliplatin.
The folate-based TS inhibitors were
developed to overcome one of the problems inherent in the use of5-FU, which
is that the inhibition of TS could be
limited if folate levels are low. 5-FU is
believed to work by conversion within
the cell to 5-fluorodeoxyuridine, which
forms a covalent complex when bound
to TS with the folate substrate. TS plays
a rate-limiting role in DNA synthesis.
The oral fluorinated pyrimidines are
essentially modifications of5-FU, aimed
at improving efficacy and toxicity. Tegafur,
for example, is a prodrug which is converted to 5-FU by hepatic microsomal
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963