JOHN POSS should have been dead months ago. In March last year, the
53-year-old found he had an incurable form of gastrointestinal cancer. It was
spreading fast, eating him alive. When he arrived in Boston six months later to
take part in a clinical trial of a promising new drug, he couldn鈥檛 even walk the
four blocks from his hotel to the hospital.
The drug saved his life. After just 30 days, his tumours had almost halved in
size. Two months later he was back playing golf. Today there鈥檚 still no sign of
the cancer returning. And he鈥檚 not alone. The drug, Glivec, has produced so many
successes that the US Food and Drug Administration fast-tracked its approval,
allowing it to come to market just two and a half months after the review
process began. That鈥檚 the fastest endorsement for a cancer medication in the
agency鈥檚 history. Approval in Britain followed last month.
It鈥檚 no surprise that the world鈥檚 media leapt on the feel-good tales of such
patients, hailing Glivec as a miracle cure. Here, at last, it seemed we had
living proof that the 鈥渕agic bullet鈥� approach works鈥攖hat it is possible
for a drug to seek out and destroy malignant cells without harming healthy
tissue. Gone would be the distressing side effects of radiation and
chemotherapy, the hair loss, nausea and infertility. A new era in cancer
treatment seemed to be dawning.
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But well before the media hype, those working closely with the drug were
coming to see its limits. For every John Poss, there鈥檚 another patient with a
different incurable cancer that Glivec can鈥檛 touch. Sometimes patients would
relapse after a promising improvement. Some didn鈥檛 respond at all. The drug hit
the news again鈥攖his time with stories of dashed hopes.
But ironically, it is Glivec鈥檚 failings as much as its successes that now
seem to be driving the revolution that cancer treatment so desperately needs.
Such a wave of excitement and introspection has not swept through the field in
years. Understanding why some patients taking Glivec relapse has led to a deeper
understanding of how cancers work, and how they might be beaten. The drug might
not give us the simple miracle cure we were hoping for, but it might well help
scientists find ways to make cancer something we can live with.
Glivec is the first of a new breed of drugs that embody the 鈥渟mart bomb鈥�
approach to treating cancer. 鈥淚t鈥檚 a proof of principle,鈥� says Stephen Nimer,
head of haematological oncology at the Memorial Sloan-Kettering Cancer Center in
New York. 鈥淭his is an example of how understanding the biology of the disease
allows you to develop treatments specific to the disease.鈥�
Decades of research have allowed scientists to discover that cancer begins
deep inside the molecular machinery of a cell: first one genetic mutation, then
another, and so on until the gene products that provide the usual checks and
balances to cell division go awry, and the cell careers down the path of
uncontrolled, cancerous proliferation.
But knowing that the accumulation of mutations can lead to cancer is one
thing, counteracting their effects is another. The most effective therapies are
still chemotherapy agents that do not discriminate well between cancerous and
healthy cells. 鈥淲hat makes Glivec different is that you can attack something
that is unique to cancer,鈥� says Larry Norton, president of the American Society
of Clinical Oncology.
Glivec is here today mostly because of the efforts of Brian Druker, a
professor of medicine at the Oregon Health and Science University in Portland,
who in 1993 was investigating treatments for a type of cancer known as chronic
myelogenous leukaemia.
CML begins as a straightforward cancer, in which a single mutation in white
blood cells is enough to start the process. The disease is caused by a very
specific exchange of DNA between two chromosomes, always numbers 9 and 22. The
swap, known as a translocation, unites two unrelated genes, called BCR
and c-ABL, to make a hybrid gene. The product of this gene is a novel
and dangerously overactive protein鈥攁 fusion of two previously harmless
ones. The fusion protein, BCR-ABL, directly activates the signalling pathway
that tells the cell to proliferate.
Druker spent hours testing synthetic compounds sent to him by a scientist at
what is now the pharmaceuticals company Novartis. His goal was to find a
molecule that killed the leukaemia cells but left healthy cells intact. After a
few weeks of screening, one compound labelled STI 571, now known as Glivec,
emerged as the most promising. 鈥淚t was absolutely clear that STI 571 was killing
cancer cells,鈥� says Druker.
Researchers now know how. Glivec is a very small molecule that can percolate
through the cell membrane and lodge in a pocket of the BCR-ABL fusion protein
where the energy-carrying molecule ATP normally docks. The pocket is crucial to
the activity of the protein, an enzyme that belongs to family known as tyrosine
kinases. When tyrosine kinases are activated by ATP they send signals through
the cell. But if Glivec sits in the pocket, ATP can鈥檛 fit in, so the enzyme鈥檚
activity is blocked
(see Diagram).
On 5 April, Druker reported the drug鈥檚 performance in clinical trials in the
prestigious New England Journal of Medicine. After taking Glivec, a
whopping 98 per cent of patients in the early stages of CML, whose cancer had
not responded to the standard treatment with interferon, went into remission.
Those numbers dwarf those observed with any other available treatment. Patients in
the advanced phase of the disease, generally considered incurable unless they
undergo a bone marrow transplant, also responded to Glivec, at least
temporarily.
It just so happens that Glivec can also attach to the pocket of another
tyrosine kinase called c-KIT, which when mutated turns healthy stomach cells
into a rare gastrointestinal stromal tumour, or GIST鈥攖he cancer that Poss
had. Some 85 per cent of GIST patients who take Glivec stabilise within weeks,
and 60 per cent see their tumours shrivel into oblivion. No wonder, then, that
Glivec is widely considered a miracle drug for treating CML and GIST鈥攁s
close as researchers have come to having a magic bullet in their armoury. The
question is, will that magic bullet approach work for other tumours?
Pharmaceuticals companies are certainly betting on it. But it won鈥檛 be the
same molecule every time. Dozens of 鈥渟mall molecule鈥� drugs are being developed
in the hope that they will inactivate the proliferation signals specific to
other cancers, and a handful of clinical trials are taking place. But as
promising as these agents seem, it is becoming clear that drug resistance is
inevitable.
With Glivec, resistance develops if patients begin treatment later in the
disease during the phase known as blast crisis, when white blood cells
proliferate rapidly. Many patients in this late phase initially do well with
Glivec, but then relapse. Recent studies explain why. Rapidly dividing cells
provide the perfect environment for mutations to accumulate. Any mutation that
affects the ability of Glivec to bind to its target protein would make some
cells insensitive to the drug, and these cells rapidly take over the population.
Suddenly, the drug becomes useless.
The fact that resistance emerges when Glivec is given in the late phase of
CML, and not during the early phase, has important implications for the
treatment of other cancers. By the time most common cancers鈥攂reast,
prostate, colon and lung鈥攁re diagnosed, they are at a stage akin to CML鈥檚
late phase. By this time multiple mutations have occurred, so several different
signals telling the cells to proliferate are being sent. 鈥淚n solid tumours there
are probably a number of abnormalities, so just turning off one switch is not
likely to be sufficient,鈥� explains Anthony Murgo from the National Cancer
Institute in the US.
In lab studies of cells from a type of lung cancer which is partially
dependent on c-KIT (the same receptor protein whose mutation leads to GIST),
Glivec only gets you so far, says Geoffrey Krystal of the Medical College of
Virginia. 鈥淭he cells slow down but don鈥檛 keel over and die, because they鈥檙e not
completely dependent on that receptor.鈥� Most tumours, Krystal says, are like a
car that can run on gasoline, ethanol or compressed natural gas. 鈥淚f your
gasoline runs out, you can still use natural gas.鈥�
Because of these complexities, researchers believe that none of the small
molecules in the pipeline will ultimately be used as single therapies to treat
the most common types of cancer. Instead, experts are beginning to propose that
using a cocktail of specific agents might be the key, each tailored to target
one component of the pathway that turns that cell cancerous. In the future,
cancer might become a chronic but survivable disease, treated with a drug
cocktail just as AIDS is today.
It鈥檚 not a new idea. Doctors have been treating patients for years with
combinations of drugs, mostly chemotherapy agents. But until now a major
obstacle has been toxicity, since by their very nature many of the traditional
medications are quite noxious. The difference between saving patients and
killing them is just a few doses. Small molecules with specific targets are
likely to be tolerated better, experts believe, even when given in
combination.
Extended family
In addition to the binding sites on BCR-ABL and c-KIT, the targets of small
molecule drugs so far include a handful of other enzymes of the tyrosine kinase
family. Glivec actually blocks a third member of that family, called the
platelet-derived growth factor receptor.
AstraZeneca is running several clinical trials with Iressa, a small molecule
that inhibits the receptor for a signalling molecule called epidermal growth
factor, which is overactive in about 30 per cent of human cancers. Another small
molecule called SU5416 blocks tyrosine kinase activity and is also an
鈥渁ngiogenesis inhibitor鈥�, meaning that it prevents the growth of the blood
vessels that are vital for keeping a solid tumour alive.
What鈥檚 exciting about these new agents, says Nimer, is that they are coming
onto the market at the same time as many powerful diagnostic tools. 鈥淏ecause of
the human genome project and gene chip technology, we鈥檙e now able to look for
thousands of mutations in cancer all at once,鈥� he says. Soon, a researcher will
be able to create a profile of each patient鈥檚 cancer to determine which cellular
receptors and proliferation signals are mutated. Then combination therapies
could be tailored to that particular tumour
(快猫短视频, 4 November 2000, p 46).
Cancers will no longer be classified according to which tissue they
come from. Their molecular fingerprints will identify what makes them tick and
the type of therapy that could destroy them.
But as vital as it would seem for combination trials of small molecules to
start as soon as possible, the truth is that not one clinical trial seems to
have done so. The FDA has not yet approved the majority of these novel drugs,
and researchers claim this means companies are reluctant to sponsor combination
trials before their candidate is approved as a single agent.
Some pressure is apparently coming from the National Cancer Institute to
start combination trials, but it won鈥檛 comment any further. 鈥淚 think that in
three or four years, as more of the drugs get approved, we will have freer
access to do the studies,鈥� Krystal says. For the moment, investigators are
testing a different kind of cocktail approach, which is to combine one small
molecule candidate with a more traditional agent, such as chemotherapy or
interferon.
As is often the case in medicine, the real obstacle may be money rather than
science. At $2500 a month, or 拢1550 in Britain, not everyone will
be able to afford Glivec鈥� and it鈥檚 not clear how long a successful course
of treatment would have to be. In an unprecedented move for the pharmaceuticals
industry, Novartis made the drug available to thousands of CML patients in
Britain and the US before the drug was approved. Since approval in the US, the
company has also provided Glivec to patients who have no insurance鈥攁
costly exercise, but great PR. In Britain, the National Institute for Clinical
Excellence is expected to issue national guidelines for the drug鈥檚 use next
August. Most commentators expect NICE to conclude that the drug is
cost-effective, and so allow it to be prescribed on the NHS. If so, the drug
company鈥檚 gamble will have paid off.
It remains to be seen whether other companies will follow this lead and make
their own small molecule drugs widely available. The lesson from Glivec is that
we need them. They could be the last barrier to changing cancer from a life or
death disease to an illness that we can live with. 鈥淚鈥檓 very optimistic about
the future as we match the right drug to the right patients,鈥� says Druker. 鈥淲e
can make cancer a highly treatable and preventable disease.鈥�