Front page article in today's National Post on low dose chemo in conjunction with Angiogenesis inhibitors. Everyone should read. A lot of it comes from a press conference with Dr Kerbel (from Aeterna's scientific advisory board).
nationalpost.com
In mice and men, less
can be more
Many cancer specialists have
thought they had reached the
summit in the search for a cure for
the killer, only to be disappointed.
Now, the medical community is
buzzing over a new approach that
focuses its attack on the blood
vessels that allow cancer cells to
grow, using low, continuous doses
of chemo and other drugs. Patients
are clamouring for the treatment.
But doctors are cautious, fearing
there may be hidden dangers
Brad Evenson
National Post
It began in the
eye of a rabbit.
In 1972, Dr.
Judah Folkman,
a brilliant
surgeon at
Children's
Hospital in
Boston, put a
cluster of
human tumour
cells onto a
rabbit's cornea
to see if they
would grow. In
theory, the cells
should have
died. The
cornea is
barren of any
blood vessels
required to
nourish a
cancer. Instead,
something
remarkable
happened.
Like baby
snakes, tiny
capillaries
began to grow
into the eye,
drawn by some
invisible force
to the tumour
cells.
This is
angiogenesis --
the birth of
blood vessels.
It usually only
happens to
embryros in the
womb.
Yet as Dr.
Folkman
watched, the
microscopic
blood vessels
grew and grew.
When they
reached the
human cells, a
tumour began to
grow
uncontrollably.
This was a
pivotal moment
-- the birth of a
cancer.
As the tumour grew, Dr. Folkman asked himself:
What if angiogenesis could be blocked?
Today, two key studies published in Cancer
Research and the Journal of Clinical Investigation
suggest it can, starving tumours of their lifeblood
by a combination of low-dose chemotherapy and
new anti-angiogenic drugs pioneered by Dr.
Folkman. The treatment has the potential to save
countless lives.
Some scientists have dubbed it "metronomic
dosing," since patients would get drugs at regular
intervals, without stopping, like a pianist keeping a
steady, metronomic beat.
The low doses of chemotherapy drugs could mean
that hair loss, nausea, anaemia and lowered
resistance to infection could become an unlamented
chapter in medical history.
The news is music to the ears of many veteran
doctors.
"In my 20 years of cancer research, I've never
heard anything that is this exciting, and that I feel
has such promise of working," said University of
Toronto medical professor Dr. Cornelia Baines,
one of the world's top breast cancer experts.
If the treatment works in humans as well as it has in
laboratory mice -- and it has helped a few
desperate patients already -- Dr. Folkman is
virtually guaranteed a Nobel Prize.
Of course, it's a big If.
As Dr. Folkman is fond of saying, "The good news
is that if you're a mouse and you have cancer, we
can take good care of you. But men are not mice."
---
The history of cancer therapy is one of false
summits.
At least 12 times this century, scientists have
proclaimed a major cure for cancer, only to find the
tumours still growing.
Radiation, chemotherapy, interferon,
immunotherapy, monoclonal antibodies, therapeutic
vaccines and gene therapy are only a few of the
approaches that have not lived up to their early
hype.
Now the spotlight is on anti-angiogenesis.
So what's different this time?
The key distinction is anti-angiogenesis does not
attack cancer cells, one of the most elusive targets
in nature. It attacks cells that form blood vessels.
"We have been taught as oncologists or cancer
researchers for 50 years to think about the
differences between cancer cells and normal cells,
find a particular difference ... then find a drug that
will exploit that difference," says Dr. Robert
Kerbel, a Toronto scientist and co-author of the
study published today in The Journal of Clinical
Investigation.
"Then, voila. We have a therapy. And that idea
often works, for a while, in patients. But the
depressing thing is that cancer cells always seem to
find a way to get around that therapy."
It was a heartbreaking scene that Dr. Folkman
witnessed thousands of times as a young chairman
of the department of surgery at Children's Hospital
in Boston in the late 1960s. So he kept a small
laboratory to pursue his interest in angiogenesis.
His theory was simple: Cancers cannot grow
beyond the size of a dried pea without a dedicated
blood supply. The key is blocking angiogenesis.
But in the chauvinistic world of cancer scientists,
the idea of a surgeon -- a mere doctor -- breaking
new ground met with sneers. He was branded a
fool and worse by some scientists. Obtaining grants
to fund his research was difficult. And it was
almost impossible to attract good scientists in
training to work with him.
"In the 1970s, professors dissuaded their best
students from coming to work in my lab," he says.
Yet during the next 20 years, Dr. Folkman and his
growing band of scientific disciples put together
many pieces of the puzzles of angiogenesis. For
example, experiments showed the invisible force
that attracts blood vessels to tumours is a group of
hormone-like substances called growth factors,
such as Vascular Endothelial Cell Growth Factor,
or VEGF.
"What happens is that cancer cells produce lots of
VEGF," explains Dr. Kerbel.
Recent evidence shows that VEGF's most important
function may be as a protective shield, saving new
endothelial cells from harm by chemotherapy
drugs.
So scientists began hunting for drugs that blocked
growth factors.
A significant breakthrough came in 1994, when a
post-doctoral student in Dr. Folkman's lab named
Michael O'Reilly isolated one of the most potent
natural inhibitors of growth factors, which they
named angiostatin. Two years later, the lab isolated
another such substance, called endostatin.
In November, 1997, the lab reported in the
scientific journal Nature that angiostatin and
endostatin work better in concert than alone at
blocking new blood-vessel growth -- in mice.
Six months later, a casual dinner remark by Nobel
laureate James Watson, who co-discovered the
structure of DNA, blew this Nature study onto the
front pages of The New York Times. Dr. Watson
had bragged, "Judah is going to cure cancer in two
years."
The next week, the lab logged over 1,000 calls a
day from cancer patients or their families
demanding the "cure."
Dr. Folkman was appalled.
"Many different substances have been shown to
inhibit cancer in mice over the years, but
unfortunately, so far not all of them have worked as
well in people," he told skeptical reporters.
A prime example of this tragic reality is
interleukin-2. In the 1980s, this drug was very
successful in treating tumours in mice. But later,
studies in people showed that interleukin-2 caused
significant side effects, such as severe drops in
blood pressure and the leaking of fluid from blood
vessels. These were not predicted based on the
mouse studies.
None of this mattered in 1998. When The New
York Times story hit the stock market, shares in
Entremed, which owned the process to make
endostatin, shot through the roof.
Predictably, Dr. Folkman tried to dampen
expectations.
"I don't think angiogenesis inhibitors will be the
cure for cancer," he told reporters.
"But I do think that they will make cancer more
survivable and controllable, especially in
conjunction with radiation, chemotherapy and other
treatments. I'm very excited to see how they will
work in people."
What Dr. Folkman kept silent about was a thrilling
experiment underway in his lab. It could prove Dr.
Watson's casual remark was breathtakingly close to
the truth.
---
Cancer is sometimes called the "transformed cell."
When a cell becomes cancerous, it begins to divide
uncontrollably. But it does not make two exact
copies. Instead, because its DNA is "unstable,"
each new cell is subtly different.
"Cancer cells have a plethora of these genetic
abnormalities or derangements," says Dr. Kerbel.
"They amplify certain genes, they rearrange other
genes, they mutate some, they turn some off, they
turn some on, they lose parts of chromosomes, they
fuse parts of chromosomes, they have extra copies
of certain chromosomes, they duplicate some parts.
It's bizarre. It is really quite bizarre."
In some ways, tumour cells are like the AIDS virus,
which mutates quickly, making it an elusive target.
So scientists took aim at cell division.
Using toxic chemicals, they blocked the processes
tumour cells use to divide. But this chemotherapy
has serious drawbacks. To begin with, it cannot
distinguish between healthy and malignant cells. It
attacks all rapidly dividing cells.
Since hair follicle cells, gut mucosal cells and
bone marrow cells also divide quickly, toxic
chemotherapy causes hair to fall out, nausea,
anemia and lowered resistance to infection. This is
why chemotherapy is given in its current form; after
receiving the maximum tolerable dose of a toxic
drug, the body needs time to recover.
But chemotherapy often stops working.
For example, ovarian cancers in women often
shrink dramatically when exposed to high-dose
chemotherapy. But they soon return in a more
aggressive form. When confronted with the same
chemotherapy drugs, they simply keep growing.
The tumour has acquired resistance.
In the mid-1980s, a University of Toronto
biochemist named Victor Ling discovered why this
occurs. Tumour cells develop a mechanism called
p-glycoprotein to literally pump chemotherapy
drugs out of their bodies. Once activated, this
protein pump works not just against one drug, but
virtually all of them. This is called multi-drug
resistance.
"Actually, the whole idea of multiple-drug
resistance is a very old observation," says Dr.
Ling, now vice-president of research at the B.C.
Cancer Agency.
"But it was a surprise to find it associated with a
single gene, or a single protein."
Since then, other such protein pumps have been
discovered, a disheartening prospect for many
scientists, which led many of them to begin looking
elsewhere for a way to kill cancer.
But in 1990, one of Dr. Ling's colleagues in
Toronto, Robert Kerbel, was thinking about drug
resistance in a new way.
"An interesting phenomenon is that when a cancer
recurs, the chemotherapy drug has no effect," says
Dr. Kerbel.
"It has grown drug-resistant. At the highest possible
dosage, the tumour simply keeps growing. It
progresses right through the therapy. But hair still
falls out, bone marrow dies and gut lining is killed,
causing nausea. In other words, those cells are still
sensitive to the drug. In fact, sometimes the side
effects can get worse, rather than diminish."
Dr. Kerbel wondered, why don't the endothelial
cells that form the tumour's blood vessels get killed
by chemotherapy?
After all, they divide rapidly, although not as fast
as tumour cells. They have weak membranes, too,
and don't stick together very well.
Even if the resistant tumour could survive in a sea
of chemotherapy drugs, Dr. Kerbel believed the
endothelial cells should die.
He mentioned this conundrum to Dr. Folkman.
"You know, I don't understand," he began.
"There should be this good side-effect of chemo.
But obviously it doesn't happen."
Dr. Folkman said little at the time. But six years
later, he told Dr. Kerbel that his lab had solved the
problem.
"Bob, you know what?" he said excitedly.
"It turns out that when you look very carefully, at
least in mice ... you can see evidence not just of
tumour-cell death but also of endothelial-cell death
in the tumour's vessels."
But Dr. Folkman had another, more arresting
observation.
"In the rest period, which is about three weeks, a
lot of that damage is reversed," he said.
"A lot of the dead cells have been replaced. So in
other words, the potential of the anti-angiogenic
effect of the high-dose chemotherapy has been lost
because of this rest period."
This was stunning.
Could millions of failed chemotherapy patients
have died because of this three-week rest period?
It was possible.
---
For many patients, chemotherapy is a living hell.
Beyond hair loss, nausea, infections and other side
effects, it often fills people with a sense of dread
and hopelessness. It also works in many cases. Up
to 80% of testicular cancer patients, for example,
can be cured by chemotherapy and surgery. Up to
70% of childhood cancers are treatable with drugs,
surgery and radiation. Anti-nausea medications
have been a remarkable success. These days, some
patients even keep their hair.
However, no patient on Earth could possibly
survive for long if treated continuously with
chemotherapy drugs, and that was what Dr.
Folkman was suggesting -- no interruptions that
would allow the tumour blood vessels a chance to
repair themselves.
But then a research fellow in Dr. Folkman's lab,
Dr. Timothy Browder, came up with the idea of
giving chemotherapy at low doses, once a week.
"Less could be more," he said.
In a striking experiment, the researchers put
drug-resistant breast and lung tumours into a group
of laboratory mice. Then, every six days, they
treated the mice with about one-third the
conventional dose of a drug called
cyclophosphamide.
Slowly but surely, the tumours responded, until
they almost completely disappeared.
They were being starved.
"Can you imagine how simple that is?" marvels Dr.
Kerbel.
"They've been actually able to reverse the
drug-resistant phenotype -- the sort of thing that Vic
Ling has been working on for years -- simply by
altering how you give the chemotherapeutic drug."
When an anti-angiogenic drug called TNP-470 was
added, the tumours were eradicated.
The excitement in the Boston lab was palpable.
While Dr. Folkman was fielding media calls about
angiostatin and endostatin that arose from The New
York Times article, a new potential therapy for
cancer had quietly arrived. Less was more.
---
It was the case of a little boy dying of cancer that
makes up the next stage of the story.
In mid-1998, Dr. Giannoula Klement, a Toronto
paediatric oncologist, was planning a low-dose
chemotherapy experiment with Dr. Kerbel. He
wanted to use breast tumour cells, but she wanted
to use neuroblastoma cells, the cause of a painful
and often fatal childhood cancer that grows in parts
of the nervous system.
And she wanted to try the chemotherapy drug
vinblastine.
Derived from the Jamaican periwinkle plant,
vinblastine is a common drug first used in
leukaemia and non-Hodgkin's lymphoma.
Discovered by Canadians, Robert Noble and
Charles Beer, it's been around since the 1950s.
Why neuroblastoma? Why vinblastine?
"There had been a child who had responded to it in
a totally unexplained way," explains Dr. Klement.
The Toronto boy had neuroblastoma that was
resistant to drugs.
He'd already failed chemotherapy with vinblastine
and other toxic drugs at progressively higher
dosages. Finally, doctors gave him the ultimate
treatment: a super-high dose of chemotherapy and a
bone marrow transplant. It failed.
The doctors had nothing else to offer.
"We put him on a low dose [of vinblastine] and
surprisingly, he got stabilized," says Dr. Klement.
Many doctors have similar stories. Patients who
are given a mild dose of chemotherapy as a
palliative treatment to reduce their suffering as they
die often survive much longer than expected.
When she began a research fellowship in Dr.
Kerbel's lab, Dr. Klement wanted to find out why
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