[MOL] Killing Cancer [00226] Medicine On Line


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[MOL] Killing Cancer



Dear Friends:  Found this and thought it may be of interest to many of our
moler friends.  Lillian

Killing Cancer
New drugs can cure mice, thanks to advances in understanding the disease's
basic biology. But cures for people are still years away 



BY SHANNON BROWNLEE AND NANCY SHUTE



Like any scientist whose work has been mired in controversy, Judah Folkman
dreamed of proving his critics wrong. But he didn't plan on success
unfolding quite this way. For two decades, he'd endured the ridicule of
colleagues, who called him a clown and said his theory of cancer--that
malignant tumors needed a blood supply in order to grow--was "dirt." The
surgeon and cell biologist at Children's Hospital in Boston persevered
nonetheless, spending mornings in surgery and afternoons hunched over a
laboratory bench. Finally, after years of laborious and often frustrating
research, Folkman, 65, had in hand two compounds that could wipe out large
tumors in mice by cutting off their blood supply, proving his theory and
opening the possibility of a revolutionary new way of treating cancer.

But when the New York Times featured his work on the front page last week,
Folkman suddenly got far more attention than he'd ever bargained for--or
wanted. In the next days, headlines across the country blared, "Cancer
Cure." Share prices soared on the stocks of a dozen biotechnology companies
hoping to bring Folkman's drugs and similar compounds to market (box, Page
64). Interview requests poured in to Children's Hospital from media outlets
around the world. And phones and fax machines in Folkman's office were
jammed by up to 1,000 calls a day, many of them urgent pleas from desperate
cancer patients and their relatives, hoping for a chance to try the new
drugs.

There was only one problem: Folkman's drugs, called angiostatin and
endostatin, are not the "cure" for cancer--at least not yet. The drugs work
spectacularly well in mice, shrinking cancers that would be the equivalent
of a 1-pound tumor in a human being. But, as one doctor said, if curing
mice were all that was needed, the war on cancer would have been won long
ago. Folkman's drugs are the most potent among a throng of similar
compounds discovered in the last decade, all aimed at choking off the
growth of blood vessels around a tumor, causing it to shrink. But the new
drugs have many hurdles to clear before they can begin helping
patients--not the least of which is to be produced in quantities large
enough to be tested in people. There is no guarantee they will work in
human beings, or work as well as they do in mice. The road to eliminating
cancer is littered with failed drugs that once were hailed as cures. And
even if the drugs are found to be effective, it will be several years
before doctors can prescribe them for their patients. As Folkman himself
wearily repeated over and over again last week, the only sure bet is: "If
you are a mouse with cancer, we can take good care of you." 

"Terrifically exciting." That said, most cancer researchers believe
Folkman's discoveries truly are revolutionary and that they do in fact
offer a novel strategy for curing cancer--though the "cure" may not come as
quickly as the public would like. "This is terrifically exciting," says
Helene Sage, a cell molecular biologist at the University of Washington. At
a meeting in Bethesda, Md., late last year, Folkman presented data that
prompted Richard Klausner, director of the National Cancer Institute, to
give the drugs the highest priority for clinical testing. Even Folkman
himself says, "I've been waiting for results like these my whole life."

Some of the enthusiasm among scientists stems from the fact that Folkman's
drugs are helping to validate scientists' efforts over the last 30 years to
understand cancer's basic biology. When Richard Nixon declared war on the
illness in 1971, biologists knew precious little about how cancer worked on
a cellular level, and oncologists had only the blunt tools of radiation,
surgery, and chemotherapy to work with. Oncologists still don't have a lot
of weapons at their disposal, but new understanding has spawned promising
treatments, including gene therapy and monoclonal antibodies, the first of
which went on the market late last year.

The insight that inspired Folkman to begin his search came long before
biologists began to peer into the interior of a tumor cell. Clinicians knew
that once a tumor grows beyond a few hundred thousand cells--no bigger than
a BB--the cells at the center of the mass start to die. Folkman surmised
that to grow, tumors need blood and send out an unknown substance that
coaxes nearby blood vessels into sprouting new capillaries--a process known
as angiogenesis, from the Greek angos, for vessel. But other clinicians,
still wedded to the notion that the infiltration of a tumor by blood
vessels was merely an unimportant side effect, scoffed at the idea.

Folkman proved the skeptics wrong in 1983, when two postdoctoral fellows in
his lab purified a protein from a rat tumor that did precisely what he'd
predicted, stimulating the growth of capillaries. There are now at least 14
known angiogenic factors. They cause blood vessels to sprout new branches
and give tumors the double benefit of a rich supply of blood and proteins,
produced by blood vessel cells, that also help cancer cells grow.

Folkman reasoned that if he could somehow block the tumor's blood supply,
the cancer could be stopped. Soon after, he quit performing surgery and
focused his attention full time on searching for a protein to do just that
by inhibiting the growth of capillaries.

Serendipity. In 1985, he got a lucky break, when blood vessel cells being
cultured in the lab were accidentally contaminated by a yeast that stopped
the cells from growing but didn't kill them. Folkman's team isolated from
the yeast a naturally occurring substance called fumigillin, which could
slow down tumor growth when injected into mice, and which simultaneously
proved Folkman's principle and transformed his critics into competitors.
Synthetic versions of fumigillin have been shown safe in people and have a
weak ability to slow tumors.

Since then, Folkman's lab and others have found dozens of antiangiogenic
factors, some of which are already being tested in people, including
thalidomide, banned in the 1960s after causing devastating birth defects,
and alpha interferon, touted as a cancer cure in the late 1970s. Both these
drugs, it turns out, have antiangiogenic properties and can inhibit blood
vessel growth. Alpha interferon is now showing limited success battling
slow-growing tumors of the bone and life-threatening hemangiomas, a
childhood cancer. But the drug can't knock out tumors that are more
malignant, says Folkman. "Breast cancer would laugh at interferon."

The scientist's new drugs, by comparison, are prizefighters. Their success
rests upon a clinical observation that has baffled doctors for years: In
some patients, the largest tumor in the body seems to stunt the growth of
metastatic tumors, the tiny progeny of the original tumor that take up
residence in far-flung sites in the body. Removing the largest tumor
surgically in very rare cases allows the little tumors to spring to life,
growing so rapidly they can kill the patient before doctors can suppress
them. Folkman and his team realized that perhaps the main tumor was itself
sending out antiangiogenic factors. These substances then traveled outward,
blocking the blood supply to the little tumors and inhibiting their growth.

In the next years, this inspiration was fleshed out by the meticulous
drudgery that makes up most of scientific research. A young doctor named
Michael O'Reilly teamed up with the University of Washington's Sage and
Yuen Shing, a protein chemist in Folkman's lab, and together they poured
milliliter after milliliter of mouse blood through glass tubing, searching
for a protein that might be a long-distance blocker of blood vessels.
Eventually, they found two. O'Reilly then had the task of extracting from
mouse urine, where the proteins are plentiful, a sufficient amount of them
to treat a few mice. "He smelled so bad that his wife made him take his
clothes off before he came in the door after work," Folkman recalls.

O'Reilly's efforts paid off. The proteins, angiostatin and endostatin,
could shrink a mouse tumor the size of an almond--much too big to be killed
by chemotherapy--to almost nothing in a few days. Working in tandem, the
drugs brought about a cure. Best of all, angiostatin and endostatin seem to
home in on capillaries near cancer cells, leaving blood vessels in the rest
of the body alone, and causing the mice no apparent side effects. Unlike
traditional chemotherapy, which can make mice as well as human patients
quite ill, endostatin, angiostatin, and vasculostatin, Folkman's newest
find, appear benign. They are also, in contrast to standard chemotherapy,
likely to keep on working even if they are given to patients for many
years. Cancer cells mutate at a furious rate, and they can evolve the means
to resist most chemotherapy drugs, requiring higher and more toxic doses to
achieve an effect. Antiangiogenic factors do not seem to induce resistance
in slower-growing blood vessel cells, but Folkman admits that no one knows
precisely how they will work in humans.

Frantic calls. Last week's New York Times article is still reverberating in
doctors' offices, where phones and faxes have been ringing with calls from
patients begging for the new drugs. "These new drugs are all our patients
want to talk about," says David Van Echo, an oncologist who heads drug
development at the University of Maryland--Baltimore. "They are saying they
want to get the new drugs and they don't want the treatment they're
taking."

It is not a wish that will be granted anytime soon. For one thing, there is
hardly enough angiostatin and endostatin in the world to treat a few mice,
let alone millions of human patients suffering from cancer. And even if
there were, the drugs must first run the gantlet of clinical trials--the
careful, government-mandated tests that are the only way to determine if
new medicines are safe and effective in people. At least 25 companies are
racing to bring versions of antiangiogenic compounds to market, including
pharmaceutical giants SmithKline Beecham, Merck, and Novartis, as well as
biotech start-ups like Boston Life Sciences and EntreMed, the firm that was
founded in order to commercialize angiostatin and endostatin. Some of the
new drugs have already entered the early phases of clinical trials, which
can take from five to seven years to complete. Endostatin and angiostatin
are at least 1 years away from human tests, says an EntreMed spokeswoman,
because the company has yet to work out the kinks to produce large amounts.

Many other obstacles lie between curing cancer in mice and battling tumors
in human beings. Mouse tumors, says Martin Brown, a professor of radiation
oncology at Stanford University Medical Center, grow extremely rapidly, and
they are totally dependent on new capillaries. "I don't want to minimize
Judah Folkman's work," he says. "There's a good chance these drugs will be
active against human tumors. But it will not be as dramatic in humans as in
mice, and human tumors will shrink more slowly." Other researchers warn
that the drugs may cause side effects in people, like muscle inflammation.
And antiangiogenics might cause birth defects if a woman takes them while
she is pregnant, as other anticancer agents do.

If they finally come to market, the new drugs will join a variety of other
new cancer treatments, many of which are already being tested in humans. In
killing cancer, the key problem remains that standard cancer treatments
such as radiation and chemotherapy damage many cells in the body, not just
the cancerous ones. More recent experimental therapies tightly target newly
identified molecular and genetic pathways within cancerous cells, rather
than using the broad-spectrum attack of older therapies. Later this month,
biotech giant Genentech will unveil the first evidence that a genetically
engineered monoclonal antibody, to be marketed as Herceptin, mimics key
components of the body's immune system and shrinks breast cancer tumors in
women. Herceptin attacks the HER-2 gene, which generates a protein that
boosts cancer growth in about 30 percent of patients.

Since the 1940s, researchers also have been trying with little success to
stimulate the body's immune system to fight cancer by administering
vaccines made of malignant cells. But in the past decade, researchers have
devised vaccines, cobbled together from either whole cancer cells or pieces
of cells, which boost an immune response against the tumor. In human trials
at Jefferson Medical College in Philadelphia and elsewhere, the vaccines
have proven as successful as aggressive chemotherapy against melanoma, but
without the debilitating side effects. Dozens of similar vaccines are in
the works targeting other cancers.

One of the most promising new cancer treatments is gene therapy. In the
1970s, scientists began to figure out that mutated genes are the triggers
that turn normal cells into cancer cells, growing out of control. If the
damage could be fixed, or the bad genes could be replaced with good copies,
they reasoned, the cell proliferation could be stalled. Current gene
therapy efforts are aimed at the three classes of genes that go bad in
cancer: oncogenes, which stimulate cell growth and division; tumor
suppressor genes, which restrict cell growth; and another type of gene that
controls DNA replication and repair. Gene therapy has generated huge
interest and millions of dollars of funding, but until recently has been
criticized as overhyped, because no one could find a method for delivering
enough genes into cancer cells without producing toxic side effects.

Catch the bus. Later this month, however, researchers from the University
of Texas M. D. Anderson Cancer Center in Houston will present results
showing for the first time that gene therapy can in fact repair damaged
genes and suppress tumors. The researchers drafted the adenovirus that
causes the common cold into service as a bus, carrying the p53 gene into
cancer cells. The p53 gene puts the brakes on cell growth and forces cells
to commit suicide if their DNA is damaged, for instance by sun exposure or
smoking. Last year, the adenovirus-p53 combo was tested in almost 100
patients with head and neck cancer, and tumors shrank in almost 50 percent
of patients. "There was very little toxicity, even with monthly
injections," says Jack Roth, the thoracic surgeon who led the study. "It
was a little surprising." P53 gene therapy is also being tested on lung and
prostate cancers, and is expected to go into clinical trials by the year
2000.

Another experimental treatment, anti-sense therapy, may not drive tumor
cells to commit suicide, but it seems to slow them down. Anti-sense
molecules are threads of nonsense DNA that derail oncogenes by jamming
their message and canceling the order for growth-promoting proteins.
Anti-sense drugs are in clinical trials in ovarian cancer and others.
Research on still another substance, an enzyme called telomerase, isn't
nearly as far along, but researchers are excited about its role in
controlling the life and death cycle of all cells, including cancer cells.
All DNA strands are capped by telomeres, extra bits of DNA that snap off
piece by piece every time a cell divides. Once the telomeres are gone, the
cell stops dividing and grows old. In January, researchers at Geron Corp.
in Menlo Park, Calif., proved that the enzyme telomerase lengthens
telomeres, enabling the cell to keep dividing. Cancer cells draft
telomerase to keep themselves going. Geron and other firms are working on
ways to block telomerase in cancer cells to force them to age and die like
normal cells.

Old and new. At least a few of these new therapies are likely to make it to
the market long before Folkman's antiangiogenic drugs become available. But
none of the new treatments, including Folkman's, will put an immediate end
to chemotherapy and radiation. Instead, old and new will be used side by
side, delivering a one-two punch to tumors. "I'd love to put radiation and
chemotherapy out of business, but it's not happening anytime soon," says
John Mendelsohn, an oncologist and president of the M. D. Anderson Cancer
Center. "We're still going to need all the help we can get, at least over
the next five to 10 years."

Folkman, for his part, envisions a time when doctors will hit tumors with
an antiangiogenic drug to knock them down in size, surgically remove the
tumors, then deliver more antiangiogenics along with chemotherapy or gene
therapy to wipe out metastatic tumors. Long-term use of antiangiogenic
drugs might be able to keep some tumors dormant so they never pose a
threat. But that's all in the future. For now, the scientist just wants to
get back to the lab and resume his search for even more powerful cancer
killers.

With Laura Tangley
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