Today's WSJ has a story on oncogenes:
May 6, 1998
A New Revolution in Genetics Equips
Cancer Fighters With Potent Weapons
By ROBERT LANGRETH
Staff Reporter of THE WALL STREET JOURNAL
The war on cancer, fought for three decades marked by failure and
frustration, suddenly is in overdrive. Just a few weeks ago, reports rocked
the medical world about two drugs that show promise in preventing breast
cancer. This week, Wall Street and Main Street alike went wild over word
of a bold experimental drug that wiped out tumors in mice.
These approaches are in very early stages of development and, even if all
goes well, will require years of human testing before they can move into
widespread usage. But they underscore a much bigger story: A quiet
revolution in genetics has brought scientists closer than ever before to
finding an actual cure for cancer.
The drugs that made headlines this week use
the promising approach of blocking a tumor's
blood vessels. Even farther along in
development, however, is a whole new
generation of gene-based drugs aimed at a
strikingly broad range of cancers. Human testing is already under way for
this new arsenal, which looks to be far more powerful and far less toxic
than anything tried before.
Targeted Precisely
Some of the biggest pharmaceutical companies are pursuing the drugs,
which attack cancer in a way entirely different from chemotherapy or
radiation, the standard therapies. Where chemo and radiation assault all
cells, cancerous and healthy alike, causing severe and even lethal
side-effects, the new gene-based chemicals are precisely targeted. They
take direct aim at the genetic machinery inside malignant cells to disable
defective or mutated genes that provide the marching orders for
unchecked growth.
Players and Progress
An arsenal of new gene-based drugs has begun human trials
Target
Company
Status of Testing
HER2
Genentech
Phase III human trials completed in
breast-cancer patients. Submitted formal
application for approval to the FDA and
could win federal approval by year end.
RAS
Merck
Phase I human safety trials began in April
1998.
Schering-Plough
Phase I trials began in late 1997.
Johnson & Johnson
(Janssen division)
Phase I tests began in early 1997. Phase
II small-scale tests for effectiveness in
humans may begin soon.
Bristol-Myers
Squibb
Preclinical testing. Phase I human trials
could begin soon.
EGFR
Pfizer (with
partner OSI
Pharmaceuticals)
Phase I testing started in 1997.
Zeneca
Beginning Phase II trials.
Novartis
Close behind Pfizer and Zeneca.
Warner-Lambert
Preclinical testing.
PDGF
Sugen
Phase III trials for treatment of brain
cancer. Phase II trials for treatment of
prostate cancer.
Note: New drugs first go through safety tests in animals before moving through
three phases of human testing to win government approval. Phase I tests for
safety in humans. Phase II tests for effectiveness in a small number of people.
Phase III tests are large-scale final trials for effectiveness and safety in humans.
Except for one far-along drug from Genentech Inc., it will still take several
years to know whether these drugs can live up to their promise. But even
guarded scientists are saying that the first new and highly effective therapy
in decades is at hand, one likely to change forever the way cancer is
treated.
"This is the dawn of the future of cancer therapy," says Richard Klausner,
director of the National Cancer Institute. And J. Michael Bishop, a Nobel
laureate in cancer research, says: "For the first time in my life, I believe we
will eventually be able to conquer cancer."
War on Cancer
The target genes that hold this promise were discovered over the past 25
years, largely the result of a surge in federally funded research after
President Nixon declared war on cancer in 1971. But only in the past five
years or so have scientists unraveled enough details of how genes operate
to try to turn them off with drugs. Now genetic targeting has become the
focus for developing most kinds of drugs, and the new anticancer
compounds are leading the way. It adds up to nothing less than a new
golden age of biology.
The war is being waged by corporate drug giants in a race for profits, their
crack research teams working in secret and often unaware of the progress
at rival labs. For years, many drug makers left most cancer research to
university and government labs because it was a costly crap shoot. Now
even some companies that never focused on cancer before are in hot
pursuit, among them Merck & Co., Pfizer Inc. and Johnson & Johnson.
The first of the gene-based drugs could win federal approval by year end.
It is Genentech's Herceptin, which attacks a virulent form of breast cancer.
Other companies are tackling a far broader range of cancers. Human
testing of gene-based weapons against cancers of the lung, colon,
pancreas and other organs has begun at Merck, Schering-Plough Corp.
and J&J. Bristol-Myers Squibb Co. and Warner-Lambert Co. are close
behind. Drugs targeting tumors in the prostate, breast, head and neck,
based on a different gene, have entered human testing at Pfizer Inc. and
Zeneca Group PLC.
Destroying Tumors
Originally, scientists just hoped gene-based cancer drugs would be strong
enough to hinder or halt tumors' growth. In a great surprise, several of the
drugs have surpassed all expectations and shown an ability to kill cancer
cells outright. In animal tests, experimental drugs from Merck and
Bristol-Myers can destroy tumors of the breast, lung or colon.
Now researchers must determine whether the drugs are both safe and
effective in humans, enduring the three phases of testing where so many
promises have been dashed. They "will undeniably be a major advance,"
predicts Robert Kramer, who heads oncology research at Bristol-Myers
Squibb. "The only question is how major." Even though some drugs are
bound to falter, researchers clearly have turned a corner in their unending
battle against cancer, thanks to a profound change in how their weapons
are developed.
For decades scientists essentially wandered around in the dark, randomly
testing thousands of natural chemicals for antitumor activity. Even when
scientists found one that killed cancer cells, they often didn't know why.
In the past decade, researchers have flicked on a light illuminating the
molecular processes by which cancer cells get the instructions needed for
rampant growth. By identifying some of the defective genes at work, they
have been able to spot vulnerabilities in the molecular mechanics. They try
to disrupt these processes with newly designed drugs -- tossing a chemical
monkey wrench into the tumor-making machinery.
This keener insight has helped researchers with other new approaches as
well, including blocking formation of the blood vessels that large tumors
must have to thrive. Another method in very early stages of study involves
"suicide genes" that are otherwise disabled in cancer cells, aiming to turn
them back on so they can tell the cell it is time to die.
"Traditional anticancer agents have been discovered through chance. We
are now going after the fundamental mechanisms of cancer," says Allen
Oliff, the top cancer researcher at Merck.
High hopes, however, have proved to be premature in the past. Cancer is
a cunning foe, coming in more than a hundred different forms and traceable
to as many different genetic defects. The list of disappointments and
outright flops in the quest to cure cancer is long and storied: monoclonal
antibodies in the late 1970s and again in the 1980s; tumor necrosis factor,
a natural protein whose promise rose and fell in the mid-1980s;
interferons, immune boosters that held out great hope a decade ago but
have only limited uses; Interleukin-2, a natural cancer-fighting protein that
made headlines in the late 1980s but proved to be violently toxic.
Tangible progress has been slow. Although survival rates for some
childhood cancers have risen and leukemia, lymphoma and testicular
cancer now can often be cured with radiation and chemo, for most other
cancers the advances have been slight. Despite tens of billions spent on
research, cancer remains the second leading cause of death after heart
disease. Eight million Americans have cancer or have survived it. Each
year it kills 560,000 people in the U.S., and 1.2 million more are
diagnosed with it.
About 96% of those who get pancreatic cancer still die within five years.
So do 94% of liver-cancer patients, 86% of lung-cancer patients and 79%
of people who get stomach cancer.
The new gene-based drugs could change all that.
To understand them, a quick primer: In each of the body's billions of cells
is a nucleus holding a genetic formula, 23 pairs of chromosomes. The
chromosomes -- long strands of DNA -- each carry thousands of smaller
segments of DNA called genes. In different types of cells, different sets of
genes are active or inactive, with each "on" gene holding an instruction
telling the cell to produce a particular protein. The on genes in, say, a skin
cell carry the code for producing the proteins needed to give it skin-like
properties.
Only several hundred of the 50,000-plus genes hold instructions for
producing proteins that regulate cell division. These are the ones involved
in cancer. Scientists have identified at least 20 defective genes that
sometimes tell cells to just grow and grow.
Their defects probably reflect a slow accumulation of genetic mutations
over a lifetime. Molecular "typos" in just one or more of the thousands of
genes in a cell can result from environmental toxins or exposure to
radiation, or they can occur randomly during cell division as new copies
are made. As more typos occur over many years, enough errors build up
to overwhelm the body's defenses against unrestrained cell growth.
What to do? Researchers, for the most part, can't tinker directly with a
flawed gene. Instead, they disable proteins that the genes order to be
made.
To accomplish that, they copy the strategy of more-conventional drugs.
Their molecules maneuver into tiny keyholes, or "active sites," that a
protein or enzyme needs to function. Plug up the keyhole and the
troublesome protein can't do its job.
When researchers first responded to the 1971 call for a war on cancer, no
one knew what caused the disease. Millions of dollars initially were spent
studying the wrong suspect, cancer-causing viruses in animals. The virus
theory failed for most human cancers.
Then in 1975 Dr. Bishop and another biologist at the University of
California at San Francisco, Harold Varmus, astonished fellow researchers
by identifying the cause of a chicken cancer: a defective gene. Although the
gene turned out to be restricted mostly to animal cancers, the work
triggered a frenzied search for genetic cancer causes in people.
The next breakthrough came three years later when an ambitious young
researcher at the National Cancer Institute, Edward Scolnick, discovered
a cancer gene in rats. He named it RAS, for rat sarcoma. Other scientists
eventually showed it played a central role in as many as 30% of human
cancers, including major killers. They found that half of all colon cancers,
90% of pancreatic tumors and 25% of lung cancers involve defective RAS
genes.
RAS now is one of three main genes the drug scientists are targeting.
About nine others are getting earlier-stage attention.
In 1982 Dr. Scolnick moved to Merck, hoping research on RAS by a
giant drug company could lead to a new way to treat cancer. Now 57 and
head of Merck's entire research operation, he vows to deliver a major
new cancer drug by the time he retires. But in the early 1980s, for Merck
and for others throwing money into the genetic approach, it was leap of
faith.
The work proved far more difficult than expected. "We wasted a lot of
time on things that were completely impossible," says Dr. Oliff, whom Dr.
Scolnick hired to head Merck's cancer program. "The first five years were
a total waste."
The problem was that they knew little about how the RAS gene actually
worked. It was like trying to repair a car engine without knowing just what
the parts did.
They know a lot more now. Normally the RAS gene carries instructions
for making a protein that perches near the inner surface of all cells and acts
as a central relay station for cell division. When growth hormones outside
the cell send chemical messengers telling it to multiply, the RAS protein
relays that directive to the cell's nucleus; otherwise, RAS stays quiet and
the cell refrains from dividing.
In cancer cells, a single chemical bead among the thousands that make up
the RAS gene is out of place; this turns the RAS protein into a monster.
Stuck in the "on" position, it continuously conveys a phantom message
telling the cell to divide and multiply.
Cancer researchers tried to create molecules that could interfere with the
RAS protein and stop it from functioning, but they couldn't find the right
spot for attack. In addition, RAS functions in all cells, so blocking it in
cancer cells risked thwarting it in healthy cells where it was needed.
That has always been a major obstacle in creating cancer drugs. Bacterial,
fungal and viral infections introduce a foreign intruder, posing a ready
target for drug design, but in cancer the enemy comes from within. The
differences between normal cells and cancerous ones are often so subtle
that drugs can't distinguish them. This is why current cancer drugs cause
such toxic side effects; they're hammering regular cells, too.
The new gene-based drugs, narrowly targeted at a cancer cell's innermost
workings, may clear this hurdle.
In 1990 two Nobel-laureate chemists at the University of Texas, Michael
Brown and Joseph Goldstein, found a promising target: a helper protein
that the RAS gene needs for forwarding messages. Called farnesyl
transferase, or FT, it is an enzyme that triggers a chemical reaction. The
search was on for a drug that could block FT.
Merck had been winding down its RAS research, but it decided to take
one last shot. By 1993, it had compounds that blocked the RAS helper
protein. But then for five long years, one after another turned out to be
toxic. "It's very frustrating because we've had compounds that [blocked
RAS] since 1993," Dr. Oliff says.
Early this year, Merck finally completed successful safety tests in animals
of a powerful anti-RAS drug -- so secret it won't even reveal the code
name. Last month it began human safety tests. If the drug is found safe, a
small efficacy test will begin, the phase II trial. If the drug clears that, the
final, Phase III trial to test for efficacy in a large group of people could
begin in a few years.
Other drug companies rushed into the fray, too, and Bristol-Myers Squibb
found a chemical that could turn off the FT helper protein in test tubes.
Animal tests showed it to be far more potent than anything the company
had tested before against cancer. In one animal test of a colon-cancer
strain that was resistant to existing drugs, the substance obliterated the
tumors 100% of the time. Human trials could begin in a few months.
Unknown to these drug powerhouses, a neighbor also was hard at work.
A mere three miles from Merck's main lab in West Point, Pa., a small
group of scientists studied the RAS gene at Janssen Pharmaceutica,
owned by Johnson & Johnson.
In 1990, a young scientist at Janssen, David End, had read a scientific
article that led him to test for anti-RAS powers in a class of drugs that
included J&J's toenail-fungus drug, Nizoral. It didn't work, so he tried
related chemicals similar to J&J's cream for vaginal infections, Monistat.
Bingo.
Janssen scientists in France later designed a compound 100,000 times
more potent than the over-the-counter product. Safety tests in humans
began more than a year ago, and the company hopes to begin efficacy
tests soon.
RAS wasn't the whole story. Also becoming a key target at some drug
companies was a gene called EGF receptor.
The EGF receptor plays a central role in division for all cells, acting as a
chemical gatekeeper on their surface. In the early 1990s, scientists learned
that the EGF receptor and the RAS protein are terminals on the same
chemical relay system. The receptor gets signals from growth hormones
secreted by other organs indicating it is time for cells to divide, then relays
the message to RAS, which dispatches it to the cell nucleus.
Normal cells have 10,000 or so copies of the EGF receptor. But many
lung, prostate and brain tumors have extra copies--as many as a hundred
times as many. That means a normal growth message is amplified
tremendously, causing the cell to reproduce madly and grow into a tumor.
Pfizer attacked this gene through a biotech partner, now called OSI
Pharmaceuticals Inc. Vastly speeding its search for a chemical to jam the
EGF receptor was new robotic testing of compounds. Pfizer and OSI
screened nearly 300,000 compounds, Pfizer's entire chemical collection at
the time, and in 1993 isolated a group of related molecules that did the
job.
But the EGF receptor strategy has a big obstacle. The risk of terrible side
effects is high because this receptor is very similar to other receptors
involved in nourishing the nerves, processing messages from insulin and
handling other critical functions. A drug that blocked the EGF receptor
might also thwart those processes, causing diabetes or even brain damage.
After years of searching, Pfizer now has a drug that can block the EGF
receptor selectively. In early human tests, it looks safe. Zeneca has a
similar EGF drug that has already moved into Phase II, the initial efficacy
test.
The EGF approach may fail to kill tumors outright. But scientists hope it
will stop them from growing and spreading, thus turning some cancers into
chronic, manageable diseases.
"The enthusiasm here is incredibly high but so is the pressure, because
Pfizer has spent millions on cancer research and we still don't have a drug,"
says Michael Morin, who heads Pfizer's cancer research at a huge lab in
Groton, Conn. "It takes a long time to test a drug when you have a totally
novel mechanism."
The third gene the drug companies are targeting heavily may be the first to
yield a marketable drug. It is called HER2, and it is the one Genentech is
aiming at. HER2 is a cousin of EGFr: a growth-message relay switch that
is hyperactive in many patients with severe cases of breast cancer.
Genentech has taken on HER2 using monoclonal antibodies, the
once-promising approach that faded with the 1980s and now is making a
comeback. They are clones of human antibodies that target a single
protein.
A lot of the credit for Genentech's drug goes to a researcher at the
University of California at Los Angeles, Dennis Slamon. Genentech
scientists exploring new genetic-splicing techniques in the 1980s sent him a
clone they had produced of the HER2 gene, not knowing what its function
was. Dr. Slamon, who was looking for genes that might be involved in
cancer, compared the cloned gene and the protein based on it with tumor
samples from patients with breast cancer. He found abnormally large
quantities of the HER2 protein in about 30% of breast-cancer tumors,
including the most virulent.
He urged drug makers to attack this gene by designing a monoclonal
antibody that would bind to the HER2 protein and block it. Most
companies didn't bite. The monoclonal method had fallen from favor, and
drug companies knew how easy it was to spend millions working on
cancer drugs and get nothing.
Top officials at Genentech, too, were highly skeptical, but a handful of
scientists there kept the research going for years. Finally, their work
produced the genetically engineered drug that has now gone through all
three phases of human testing. Herceptin has been given to about 400
women with a virulent form of breast cancer, and in combination with
chemotherapy it helps at least some of the time. A few women on the drug
remain alive and well several years after being told their breast cancer was
terminal.
Detailed trial results will be released May 17. This week, Genentech
applied to the Food and Drug Administration for approval to sell
Herceptin, which the company's chief medical officer, Susan Hellmann,
calls "a breakthrough by any criteria."
How much longer patients will live thanks to such gene-based drugs won't
be clear for years. The new chemical weapons are so different that testing
poses immense challenges in deciding what doses to use, for how long,
and in which patients. Scientists may end up having to combine several
types into a cocktail that blocks the products of several defective genes.
But even with all the caveats, legions of veteran cancer researchers have
the palpable sense that a revolution in cancer treatment is at hand -- that
the notion of an outright cure, someday, has become an attainable goal.
"It's unpredictable what will happen," says Merck's Dr. Scolnick. As he
and other scientists repeatedly point out, many prototype drugs, once so
full of promise, ultimately failed. But even the always-cautious Dr. Scolnick
is hopeful. It is possible, he says, that under the attack of the new
gene-based drugs "the tumors will just melt away." If that happens, "it
would be a miracle." |
