Maybe, who knows? CYPH never made Taxol chaply, never ahd an edge and now this from the front page of the WSJ: Tests by Bristol-Myers Show Therapy Shrinks Tumors That Taxol Can't Treat
By MICHAEL WALDHOLZ
Staff Reporter of THE WALL STREET JOURNAL
When German microbiologist Hans Reichenbach began investigating a
"very strange" family of bacteria in the early 1960s, he couldn't have
predicted that 40 years later his studies would steer several major
pharmaceutical companies to one of the more promising cancer drugs now
in development.
But last October, Bristol-Myers Squibb Co. initiated the first human tests
of an experimental class of drugs based in part on Dr. Reichenbach's
doctoral thesis and his career-long preoccupation with the biology,
behavior and other "peculiarities" of myxobacteria. Especially cunning
micro-organisms, myxobacteria, while invisible to the naked eye, are as
common as dirt.
Within cancer-research circles, the new drugs are being greeted as
perhaps more potent than Bristol-Myers's Taxol, a therapy widely used for
treating certain breast, ovarian and small-cell lung cancers. Initial
laboratory studies not yet made public show that the new drugs can attack
tumors unresponsive to Taxol, suggesting that they may also be effective
against tumors of the colon and prostate.
'A Very Hot Race'
Already, Novartis AG, the Swiss drug maker, is developing its own
version of the drugs. Several other academic and company labs aren't far
behind. Afraid of tipping off competitors to their progress, major drug
makers and their collaborators in university labs haven't published much
about their efforts. "We are definitely in a very hot race with
Bristol-Myers," says Paul Herrling, head of research at Novartis in Basel,
Switzerland, noting that the company that can make a better Taxol will
likely reap huge profits for many years.
"A Taxol-like drug active against more tumors than Taxol is something
we've all been searching for," says Lawrence Norton, head of the
solid-tumor division of Sloan-Kettering Memorial Cancer Center, New
York. Taxol and the closely related drug Taxotere, sold by the
French-German drug conglomerate Aventis SA, are the world's
biggest-selling cancer drugs, generating about $1.8 billion in sales in 1999
and representing about 25% of the world-wide cancer chemotherapy
market.
Developers of the new drugs are cautious about their prospects, however,
and concerned about unfairly raising the hopes of cancer patients. "Most
experimental cancer drugs crash," warns Ernest Hamel, a senior
investigator at the National Cancer Institute's Frederick Cancer Research
and Development Center, Frederick, Md., who is familiar with the drugs.
Tempering the Enthusiasm
Though enthusiastic, researchers at Bristol-Myers and Novartis warn that
the new drugs could produce toxicity levels in people not yet seen in
animal studies. Scientists say they won't know until later this year whether
the drugs will be safe, and efficacy trials won't be completed for several
years after that. Even if the drugs fail to pass scientific muster, their
discovery and development to date reflect the long-term, high-stakes
betting drug makers must make these days if they are to produce truly
innovative medicines.
The decades-long road to producing the super-Taxol drugs is one that
starts with Dr. Reichenbach's graduate-student curiosity, runs through the
serendipitous discovery of Taxol a few years later, and involves a
fortuitous finding by Bristol-Myers's arch-competitor, Merck & Co., of a
critical clue that Merck failed to follow up on -- but that led Bristol-Myers
back to Dr. Reichenbach and, eventually, to the drug.
It Grows on Trees
Taxol, derived from the bark of yew trees found mainly in old-growth
forests, was discovered by chance as part of a global screening program in
the 1960s by NCI scientists. It was first approved in the U.S. against
ovarian cancer in 1992 and against breast cancer two years later. Its
success triggered a frenzied hunt throughout the 1990s as researchers
around the globe screened tens of thousands of other organisms, trying to
find similar chemicals that provide a natural shield from predatory
microbes.
Taxol's power derives from its ability -- unique among cancer drugs -- to
block a cancer cell from dividing and growing. It does so by way of a
clever defense mechanism that fir-like yew trees use to fend off fungal
infections and other disease-causing germs.
But Taxol has its drawbacks. Some fast-dividing cancer cells can mutate
into forms resistant to the drug. Often, patients with advanced cancer who
respond at first to Taxol don't respond after several cycles of treatment
because their cells become resistant, too. Despite conducting dozens of
trials over the years, Bristol-Myers has been frustrated in its efforts to
expand Taxol's effectiveness beyond certain breast, ovarian and lung
cancers.
That's why the new drugs, broadly classified as part of a family of
chemicals known as the epothilones, hold such promise. In studies not yet
published, Bristol-Myers and others have shown that the epothilones
disrupt cell division through the same biochemical pathway as Taxol. But
for reasons scientists are only beginning to understand, the new drugs are
equally effective against cancer cells already resistant to Taxol, as well as
cells that develop resistance over time.
"For that reason alone, we think our drug is the equal of or better than
Taxol," says Frank Lee, a senior research investigator at Bristol-Myers.
Indeed, those who have studied the epothilones say they are surprised by
the new drugs' ability to overcome Taxol resistance. Says Dr.
Reichenbach: "I'm astonished, and, of course, I've had high hopes for a
very long time that the myxobacteria would lead us to important new
medicines. To be honest, though, for the longest time I wasn't sure what its
use would be, though I was certain it would be something."
Dr. Reichenbach, now 63 years old, was originally encouraged by his
professor to study the bacteria because they had "a highly developed
social life" that made them "very interesting," he says. Although the bugs
were identified in the early 1800s -- scientists thought they had found a
new type of fungi -- little else was known about them except that they
were ubiquitous.
Like a Grain of Sand
Over the years, Prof. Reichenbach and his colleagues at Gesellschaft fur
Biotechnologische Forschung, or GBF, a research institute in
Braunschweig, Germany, have scoured the planet, isolating hundreds of
strains of the myxobacteria found in thousands of soil samples from
Antarctica to Africa. They found that the typical habitat of myxobacteria is
the topmost bits of earth from environments as diverse as dune and desert
sands to fertile backyard gardens in central Europe and the midwestern
U.S.
Among the many things he has learned about the bugs is that they richly
populate "decaying plant material, including rotting wood and bark from
dead and living trees, decomposing lichens and insects and dung,"
especially of certain herbivorous mammals such as wild rabbits, hares,
deer, sheep and goats. "Myxobacteria have also been isolated regularly
from the gut content of carp," the microbiologist points out, in case anyone
wants to know. But, he notes, even a spoonful of dirt from outside his front
door has yielded several strains of the microbe.
It was, however, a spoonful of mud sent to his lab from the banks of the
Zambezi River in southern Africa that gave Dr. Reichenbach and his
colleague, Gerhard Hofle, their "Eureka!" moment in 1985.
Missing Link
By this time, Prof. Reichenbach, as he prefers to be called, was the
world's premier expert on myxobacteria. Years of study had uncovered
that myxobacteria congregate in "communities" that produce a slimy
material on which the microbes slither as their preferred mode of travel.
The excreted substance seemed to have something in it that killed other
micro-organisms, some of which the community consumed as nutrients.
But the professors still couldn't isolate the stuff within the slime responsible
for slaying the microbial neighbors.
From the Zambezi soil sample, the German researchers were able to
isolate a new myxobacteria strain they called Sorangium cellulosum,
because of its ability to degrade cellulose. Two years later, the scientists
finally separated out a powerful cell-killing chemical they dubbed
epothilone. First tested as a fungicide for potatoes and grapes, the
chemical killed the fungi but was also toxic to the plants. Tested as an
immunosuppressant agent, it also appeared -- erroneously, as later
became apparent -- to be toxic to animal cells. "For a long time nothing
much happened," Prof. Reichenbach says.
Then in 1995, there emerged from a laboratory in the U.S. the kind of
unanticipated event that so often marks important scientific advances.
Working without any knowledge of the Germans, a research team at
Merck's drug-hunting labs in West Point, Pa., found something scientists
the world over were seeking.
Environmental Expense
Though Taxol was fast becoming one of the more effective anticancer
agents, extracting it from yew trees was expensive and controversial -- the
trees are relatively rare and are home to certain forest animals. That's why
lab groups such as the one at Merck were screening thousands of plant,
marine, insect and fermentation extracts, seeking natural substances that
acted like Taxol.
By coincidence, one of the thousands of natural products the Merck lab
screened was an extract of Sorangium cellulosum. Merck obtained a
sample from a former colleague of the Germans who had moved to
Kansas to teach at Emporia State University and was storing a batch of
the bacteria in the basement of his home. Merck scientists soon found that
the extract worked just like Taxol.
Only after scanning the research literature for any previous references to its
chemical structure did the Merck scientists realize that the Germans had
already found the Taxol-like chemical seven years earlier. Merck
published its findings in 1995 but ultimately decided not to pursue a
Taxol-like drug, because it had other cancer projects in the works.
The first that Prof. Reichenbach heard of Merck's discovery was from
officials at Bristol-Myers, who, shortly after reading the Merck research
paper, contacted GBF and asked to license the German patent rights to
the chemical.
Stunted Growth
What excited Bristol-Myers and the Germans was that myxobacteria
colonies used epothilones to attack their enemies with a biochemical
strategy identical to the one employed by Taxol. Taxol's power derives
from its ability to slip inside the nuclei of cells and fasten tightly onto
tubules, rod-like structures that transport DNA from a parent cell to its
offspring during cell division. Bound by Taxol, the tubules become fixed in
place, unable to carry the DNA to new cells; thus, cell division -- and
tumor growth -- is thwarted, often even terminated.
By 1995, Bristol-Myers had figured out how to manufacture Taxol without
using yew bark, so an alternative source was no longer a driving need. But
Bristol-Myers now had a different concern: cancer cells that developed
resistance to Taxol, limiting the drug's long-term use. Company scientists
found that under repeated attacks from Taxol, some evolving cancer cells
are born with an ability to "literally pump Taxol" back out of the cell before
the drug can get to the tubules, says Renzo Canetta, vice president for
clinical oncology at Bristol-Myers.
The company immediately began mixing the epothilones in test tubes with
tumors that had mutated into forms no longer sensitive to Taxol. The
epothilone "isn't detected by the pump," Dr. Canetta says. "That may turn
out to be the key to the drug's success."
Lab Experiments
Since 1998, Bristol-Myers has undertaken an intense, secretive effort to
develop a semisynthetic chemical cousin of the epothilone. One compound
the company produced, code-named BMS-247550, has been tested
against numerous Taxol-resistant cells. In one typical study, the
researchers obtained a tumor sample from a patient who succumbed to an
ovarian cancer that had generated resistant cancer cells. The tumor was
stitched onto laboratory mice, and when they were treated with the new
compound, the tumors began to shrink.
In another experiment, researchers treated human-tumor-bearing mice with
a combination of the epothilone drug and another experimental
Bristol-Myers compound that works differently. In three of seven
instances, the Taxol-resistant tumors were eradicated. Bristol-Myers plans
to present these and other lab experiments to the cancer-research
community for the first time this spring at several scientific meetings.
Last fall, after the drug passed numerous animal-safety trials, the company
began a small series of tests in patients who had failed to respond to Taxol
or other treatments, a first step in determining if the drug is safe and useful
in people.
One idea is that patients would get Taxol until their cancer developed
resistance, and then would receive the new drug. "This way we could
prolong treatment," Dr. Canetta says, "giving the patient a greater
opportunity to fight off the cancer."
Synthetic Version
Meanwhile, a handful of researchers, also inspired by Merck's 1995
report, have been trying to produce synthetic chemicals that mimic the
epothilones but aren't covered by the German patent. Sam Danishefsky, a
medicinal chemist at New York's Sloan-Kettering cancer center, has
produced a series of synthetic versions that are expected to be tested in
people soon. K.C. Nicolaou, chairman of chemistry at Scripps Institute in
La Jolla, Calif., and a professor at the University of California, San Diego,
says his labs have "produced hundreds of analogs" of the epothilones.
Novartis has licensed the right to develop Dr. Nicolaou's drugs, but, like
Bristol-Myers, it has avoided publicizing its efforts. Nonetheless, Novartis
confirms that it began testing one of the Scripps drugs in people around the
same time Bristol-Myers launched its first human studies.
"In animal studies," Dr. Nicolaou says of his epothilone-based drug, "it
appears to be superior to Taxol, maybe even better than the epothilone
chemical." But, he adds: "Curing mice doesn't mean you can cure people.
We need to make that point as strongly as possible, and just wait and see
what happens." |
