Hope In the Lab: A Special Report; A Cautious Awe Greets Drugs That Eradicate Tumors in Mice

Keith Elis (hagbard@ix.netcom.com)
Sun, 03 May 1998 17:01:05 -0400

Copyright 1998 The New York Times Company

The New York Times

May 3, 1998, Sunday, Late Edition - Final

Section 1; Page 1; Column 1; National Desk

2186 words

HOPE IN THE LAB: A special report.

A Cautious Awe Greets Drugs That Eradicate Tumors in Mice


Within a year, if all goes well, the first cancer patient will be
injected with two new drugs that can eradicate any type of cancer, with
no obvious side effects and no drug resistance -- in mice.

Some cancer researchers say the drugs are the most exciting treatment
that they have ever seen. But then they temper their enthusiasm with
caution, noting that the history of cancer treatments is full of high
expectations followed by dashed hopes when drugs with remarkable effects
in animals are tested in people.

Still, the National Cancer Institute has made the drugs its top
priority, said Dr. Richard D. Klausner, the director. Dr. Klausner
called them "the single most exciting thing on the horizon" for the
treatment of cancer.

"I am putting nothing on higher priority than getting this into
clinical trials," Dr. Klausner said. The mouse studies are "remarkable
and wonderful," he said, and "very compelling." But he pointed out that
the studies were in mice and so, when it comes to humans, he said he
wanted to emphasize "the if's."

The new drugs, angiostatin and endostatin, work by interfering with
the blood supply tumors need. Given together, they make tumors disappear
and not return.

Dr. James M. Pluda, who is directing the cancer institute's planned
tests of the drugs in patients, said he and others at the institute were
"electrified" when they heard the drug's discoverer deliver a lecture
about the newest results. "People were almost overwhelmed," Dr. Pluda
said. "The data were remarkable."

Although the discovery of the drugs, and some of their effects, have
been reported over the past few years, Dr. Pluda said that "if people
understood how many steps ahead" the research was compared to what had
been published, "they'd be even more in awe."

But Dr. Jerome Groopman, a cancer researcher at the Harvard Medical
School, was wary. "We are all driven by hope," Dr. Groopman said. "But a
sober scientist waits for the data." And until the drugs are given to
humans, he said, the crucial data simply do not exist.

So far, the drugs are the only ones ever tested that can seemingly
eradicate all tumors in mice, even gigantic ones, equivalent to a
two-pound growth in a person. The best that other cancer drugs have done
is slow the growth of these large tumors. Mice are the traditional test
animals in cancer research.

But even the drugs' discoverer, Dr. Judah Folkman, a cancer
researcher at Children's Hospital in Boston, is cautious about the
drugs' promise. Until patients take them, he said, it is dangerous to
make predictions. All he knows, Dr. Folkman said, is that "if you have
cancer and you are a mouse, we can take good care of you."

Other scientists are not so restrained. "Judah is going to cure
cancer in two years," said Dr. James D. Watson, a Nobel laureate who
directs the Cold Spring Harbor Laboratory, a cancer research center on
Long Island. Dr. Watson said Dr. Folkman would be remembered along with
scientists like Charles Darwin as someone who permanently altered

The long trail to the discovery of the new drugs began more than 30
years ago when Dr. Folkman became obsessed by what many saw as a
quixotic notion: that cancers cannot grow beyond the size of a pinhead
unless they have their own blood supply. If he could block a tumor's
blood supply, he reasoned, the tumor should shrink to a minuscule size.

The first major break in the efforts came a decade ago when Dr.
Folkman and his collaborators found drugs that did what he envisioned.
He called them anti-angiogenesis drugs because they stopped the process
of developing new blood vessels, or angiogenesis. They slow tumor growth
in animals but do not eradicate the tumors. Early results in patients
indicate that the drugs may slow human cancers. Dozens of companies are
developing such drugs.

The results with these weaker drugs were "a proof of principle," said
Dr. Bart Chernow, a professor of medicine and dean for research and
technology at the Johns Hopkins University School of Medicine. Dr.
Chernow is a founder of Entremed, a company in Rockville, Md., that was
formed to make and market angiostatin, endostatin and other weaker drugs
that can slow cancer growth.

But the real breakthrough -- and the two new drugs -- came from Dr.
Folkman's efforts to understand a peculiar phenomenon that has been
known to cancer surgeons for 100 years: sometimes a patient will have a
single tumor, with no evidence whatsoever of metastases, the satellite
cancers that can pepper a patient's body. A doctor will remove the tumor
and all will seem fine. But then, a few months later, a whole series of
metastases will appear, grow, and kill the patient.

In 1989, Dr. Folkman proposed a reason for the effect, which he wrote
on a large white board in a room where his laboratory group had its
weekly seminars. Is it possible, he asked, that a tumor could be making
both stimulators and inhibitors of blood vessel growth? If so, the
inhibitors might travel through the bloodstream, squelching metastases.
When the large tumor was removed, it would no longer be a source of
inhibitors, allowing the tiny metastases to proliferate.

Dr. Folkman tried to get one of his doctoral or post-doctoral
students to work on that idea. "Each Friday, at our meeting," he said "I
would say, 'Here's a great experiment.' But no one wanted to work on
it." It seemed too wild, Dr. Folkman said, too unlikely to result in
findings that would end up in a scientific journal, a major goal of
young scientists.

Undertaking The Big Challenge

Then, in 1991, a post-doctoral student, Dr. Michael O'Reilly, decided
to take on the challenge. Dr. O'Reilly focused on a particularly deadly
mouse cancer that grows to the equivalent of a two-pound tumor in a

As long as mice had the large tumor, they had no signs of metastases.
But five days after the tumors were surgically removed, metastases
invariably sprang up in the animals' lungs. Within 15 days, the animals
would be dead, their lungs packed with large red tumors, like grapes.

Eventually, after arduous work in collaboration with chemists, Dr.
O'Reilly discovered that the large tumors made a substance that stymied
the growth of other tumors. This substance showed up in the animals'
urine, but was present in such minute quantities that Dr. O'Reilly had
to collect 10 quarts of mouse urine to obtain 30-thousandth of an ounce
of the mysterious substance. It turned out to be a piece of a larger and
very common protein, plasminogen, that the body uses in blood clotting.
Dr. Folkman named the new substance angiostatin.

Apparently, cells can use the plasminogen gene for two purposes: they
can use it at its full length to make plasminogen, or they can use just
a piece of it and make angiostatin. Plasminogen does nothing to stop
tumor growth. The question was, would angiostatin?

Dr. Folkman and Dr. O'Reilly discovered that angiostatin also
appears, in minute quantities, in human blood. Using outdated human
blood discarded by the Red Cross, they extracted enough angiostatin to
treat mice. Then they began their experiment.

They had 20 mice with large tumors on their backs. The investigators
removed the tumors and then injected half of the mice with angiostatin
each day and the others with salt water, as a comparison.

After 15 days, the researchers killed the mice and cut them open. As
more than a dozen scientists gathered around a table in the laboratory,
Dr. O'Reilly opened the first mouse. It had huge tumors filling its
lungs. Then Dr. Folkman checked a notebook to see what the animal had
received: salt water. They looked at the next mouse. No tumors. Dr.
Folkman checked to see the treatment: angiostatin. And so it went. All
10 of the mice that had been injected with angiostatin were free of
cancer. All 10 of those that had been received salt water had huge new

A Jubilant Celebration And a Second Discovery

The room was buzzing, the scientists were grinning. Dr. Folkman said.
Everyone in the room knew what the results meant, and they were elated.
They responded, he said, like men at a football game. "Everyone clapped
O'Reilly on the back," Dr. Folkman said.

Then the researchers found a second protein fragment, secreted by
tumors, that also squelches metastases, Dr. Folkman said. It was a piece
of a different protein, collagen 18, that is in all blood vessels but by
itself has no effect on cancer. They named the collagen fragment

"It was even more potent than angiostatin," Dr. Folkman said. If he
gave it to a mouse with a huge tumor, he said, the equivalent of one
weighing a pound and a half in a human, endostatin would shrink the
cancer down to a microscopic size.

Moreover, tumors never became resistant to endostatin, said Dr.
Folkman, who added that he had given the drug to mice with large tumors
and they had shrunk to almost nothing. He stopped the drug, he said, and
the tumors grew back. Then he gave the drug continuously for the rest of
the animals' lives. The tumors remained small and harmless and the
animals remained healthy.

Dr. Robert S. Kerbel, a cancer researcher at Sunnybrook Health
Science Center in Toronto, said he was not surprised that the cancers
never became resistant to endostatin. Tumors become resistant to
chemotherapy drugs, Dr. Kerbel said, because cancer cells constantly
reshuffle their genetic information. The result, he said, is that the
tumors spin off mutant cells that resist the drugs and, ultimately, the
tumors grow back, invulnerable.

But, Dr. Kerbel said, angiostatin and endostatin do not act on
tumors. Instead, they act on normal blood vessels that feed tumors. And
normal cells, he said, do not reshuffle their genes and so do not
develop drug resistance. That is why chemotherapy drugs continue to
devastate normal cells -- causing bone marrow suppression, loss of hair,
nausea and vomiting -- even when the cancer cells have grown impervious
to their effects, Dr. Kerbel said.

Drug Combination Knocks Out Tumors

Then Dr. Folkman discovered that he could actually obliterate tumors
in mice with his new drugs. He gave endostatin and angiostatin together,
treating mice for 25 days. To his surprise, Dr. Folkman said, "there was
no tumor left -- we couldn't even find it with a microscope." The
tumors, he said, "were eradicated."

And the drugs seem to have no side effects at any stage of life, at
least in mice, something that Dr. Folkman said is hard for researchers
to believe. But, he said, he had given mice up to four times the doses
needed to eliminate cancer and could not find any adverse effects. These
two human proteins may be, he said, "exquisitely aimed -- we do not know
why -- at cancer."

In contrast, Dr. Folkman said, mice become very ill when they receive
commonly used chemotherapy -- their hair falls out, they bleed, they
refuse to eat.

For the past four years, Dr. Folkman said, he and his colleagues have
found that all tumors responded to the drugs in the same way. Even
leukemia, a blood tumor, responds, he said, because it turns out that
leukemia needs to form new blood vessels in the bone marrow to grow.
Leukemia tumors grow on these blood vessels, "like berries on a bush,"
Dr. Folkman said, shedding cancer cells into the blood.

But Dr. Folkman is the first to urge caution in leaping to
conclusions about what might happen when patients try the drugs. "Going
from mice to people is a big jump, with lots of failures," he said.

Hopes were high for chemotherapy drugs that worked well in mice but
turned out to be less successful in people. Therapies that used the
immune system to rid the body of cancer also worked in mice but were
disappointing when they were tried in people. Gene therapy treats mouse
cancer, but has had limited success in people.

From bitter experience, most cancer researchers have learned to be
leery of what one called "that four letter word" -- cure.

Meanwhile, Entremed is working as fast as it can to produce
angiostatin and endostatin for studies in humans. Dr. John Holaday,
Entremed's president and chief executive, said his company was working
with the Bristol-Myers Squibb Company to develop angiostatin and had not
yet decided on a corporate partner to develop endostatin. The drugs are
being made in genetically engineered yeast growing in 20-gallon vats.

Dr. Pluda, of the cancer institute, said the first patients to get
the drugs would have cancers that were growing quickly and were
essentially untreatable. The institute will start by giving the drugs
separately by the end of the year, he said, then hopes to combine them.

Already, Dr. Folkman said, he gets hundreds of calls a day from
cancer patients, pleading for the drugs.

Dr. Folkman, in an interview on Friday, said one call had come from
an old friend from medical school with prostate cancer that had spread
to his bones.

"He's terrified," Dr. Folkman said. But there were no strings Dr.
Folkman could pull. He said he had to tell his friend what he told all
the other callers: "You can't get it because it isn't being made."

GRAPHIC: Photo: Dr. Judah Folkman is cautious about his cancer-drug
discovery. (Children's World)(pg. 34)

Diagram: "IN THE WORKS: Hope for a Breakthrough"
Drugs called angiostatin and endostatin occur naturally in small
quantities in the human body and work by interfering with the blood
vessels that tumors need to survive and grow. When tested together in
mice, the drugs made tumors disappear and not return.

Mice are injected with cancer
Cancer grows into large tumors on the back.

Mice injected with salt water -- In this group, cancer continues to

Mice injected with either endostatin or angiostatin -- Cancer shrinks to
almost nothing, but when treatment stops, the cancer may return.

Mice injected with both endostatin and angiostatin -- After several
weeks of injections, the cancer shrinks to nothing and does not recur.

(Sources: Dr. Michael O'Reilly, Dr. Judah Folkman, Dr. Thomas Boehm and
Dr. Timothy Browder)(pg. 34)