For all the newbies on this list. Us oldtimers have seen this before, and is
worth a reread.
Zavie
Dr. Brian Druker
[Molecules and Cancer Science: 30 Years of Discovery]
DR. BRIAN DRUKER: Thank you. It's a pleasure to be here to speak to you this
morning. What I want to take you through is a little bit of the past, a
little bit of the present, and what I see for the future.
Let me start with cancer. "Cancer" is a pretty frightening word. And perhaps
in our vocabulary, no words other than "terrorism" or "anthrax," strikes
such fear into our hearts. But for those who grapple with cancer, there's a
word even more frightening than any of those words, and that's
"chemotherapy." Although chemotherapy is remarkably successful -- it's cured
a number of diseases, such as childhood leukemia, Hodgkin's Disease,
testicular cancer -- when we think about chemotherapy, we think about the
devastating side effects. So when you walk into an oncology waiting room,
it's not uncommon to see patients who are thin, bald, or patients who are
sitting there with an emesis basin. Those are the images we have of
chemotherapy and what we do to our cancer patients.
I want to give you a glimpse of the future. And I want you to walk in my
waiting room, where we're treating CML [chronic myeloid leukemia] patients
with Gleevec. Patients like Judy. Judy came to me three years ago. She had
been diagnosed with chronic myeloid leukemia several years before, and had
been on treatment with interferon. Interferon had stopped working, and her
doctor had given her the dreaded speech. She told her, "'Judy, there's
nothing left we can do. You probably have no more than two years to live.
There's absolutely nothing we have to offer you."
She came to see me November of 1998. We were just beginning clinical trials
with, what in those days, was STI-171, and we talked about enrolling her.
She said, "'Well, before I do that, I want to take my family on a trip.
We're going to go to New Zealand and Australia, and it's the one last thing
that I want to be able to do with my family.'" We enrolled her in our
clinical trial in January of 1999 after she returned from her trip. Three
years later, she is here, doing well, and has no evidence of leukemia. She
and her husband just bought a new house. They're planning for their futures.
Sitting next to her, you might see Ladonna. Ladonna's a patient who came to
me with even more advanced disease. No one, including me, believed Ladonna
had more than days or weeks to live. Ladonna had a spleen --which normally
should be tucked up under the left side of your abdomen -- which was down to
her pelvis. It was pressing on her stomach such that she could barely eat
anything without throwing up. She was losing two or three pounds a week. She
had begun to plan her funeral and had even picked out the music that she
wanted played at her funeral.
We started her on Gleevec. Within a week, her spleen began to shrink. Within
a month, it was back to its normal size. Today, Ladonna's spending time with
her grandchildren, three of them here, including the youngest one, who is
named Will, because he was her will to live. Two years later, I still can
detect no evidence of leukemia.
This is what we've been able to accomplish with Gleevec. What I want to take
you through is how we got there by understanding what's broken in this
particular leukemia. I'm going to take you through the 40 years of cancer
research that got us to this point.
The driving force behind cancer research has been the simple mantra, if you
understand what's broken, you can fix it. Let me give you an analogy for
what we're talking about, and the analogy that I like to use is a
thermostat. Think about it: We're here sitting in this room, we're all quite
comfortable. The temperature of this room is very nicely regulated,
somewhere between 68 and 72. When the temperature falls below 68, the
thermostat turns on, provides a little bit of heat, gets to 72, then it
shuts down. Perfectly regulated. The body does exactly the same thing. Every
single day, we have to replace a certain number of cells through daily
losses. The body has a thermostat. When we need some cells, the thermostat
turns on. It replaces the exact numbers of cells we need. When it has the
right number of cells, it shuts off.
But imagine that the thermostat was broken and stayed on. The temperature
would start to climb. We'd get a bit warm and take our jackets off. The
temperature would continue to rise, and we'd get uncomfortably hot. That's
exactly what happens in a cancer. It's as though a thermostat gets stuck on.
The cells grow, they divide, they multiply, and form a tumor. That's what
cancer's all about.
So how are going to fix the problem? Well, we could replace the thermostat,
a pretty drastic measure. Our medical care system might not be able to cover
those kinds of costs. We could do something like chemotherapy. That would be
about like hitting the thermostat with a hammer, hoping it fixes it, but
probably leaving it pretty damaged.
But imagine now that you could take that thermostat apart, piece by piece,
and figure out which part is broken, and just replace that broken part.
Well, that's what we've done with Gleevec in chronic myeloid leukemia.
Before I get to that, let's think about this in a broader context. The year
2000 saw the completion of the Human Genome Project. That's like providing
us with a parts list. Now, the task for the future is going to be figuring
out how all those parts fit together, and which part is broken in which
cancer. So let me take you through how we did that with chronic myeloid
leukemia.
The story dates back to 1960. Two researchers, Peter Nowell and David
Hungerford , working in Philadelphia, were looking in the bone marrow's of
leukemia patients with this disease. They noticed a funny-looking
chromosome, a short chromosome. It ultimately became the Philadelphia
Chromosome, after the city in which they were working. Thirteen years later,
1973, Janet Raleigh, working at the University of Chicago, recognized that,
in fact, this shortened chromosome came about because of the exchange of
material between two chromosomes, Chromosomes 9 and 22.
In the 1980s, researchers recognized the consequences of that translocation.
This translocation has created what was called an oncogene. In the 1970s,
the field of oncogenes had been born. Drs. [Michael] Bishop and [Harold]
Varmus, Dr. [Robert] Weinberg, had identified that our cells contain genes
that, if they become mutated cause the uncontrolled growth of cancer
cells... If these genes are broken, it's like sticking the thermostat in the
"on" position.
Out of this field, it became clear that one of these genes had become broken
in this disease called chronic myeloid leukemia. As it turned out, it was a
member of a family of enzymes called tyrosine kinases. Tyrosine kinases are
known to regulate cell growth, and in this particular leukemia, it was as
though this switch had been stuck on, causing the uncontrolled growth of the
cancer cells.
About that same time, around 1990, animal models demonstrated that this
abnormal tyrosine kinase could cause leukemia in an animal model, and
absolutely conclusively established that this abnormality induced leukemia.
So as you think about this process, from 1970 to 1990, we had to develop
things like DNA sequencing, the field of oncogenes, the field of
understanding these chromosome translocations. All that had to develop. We
had to develop all these technologies for this to occur.
Then in the late 1980s, working in collaboration with scientists at
Novartis, a drug discovery program was initiated to begin to shut down these
abnormal tyrosine kinases, the enzymes that were causing the uncontrolled
growth of this leukemia. Out of this program came STI-571, or now Gleevec,
and we began testing this compound in 1998.
Within six months of starting our clinical trials, every single one of our
patients, taking now four pills once a day, had their blood counts return to
normal. One year later, those results, which we had originally obtained in
about 100 patients, were expanded to 1,000 patients. In May of the year
2001, Gleevec obtained FDA approval in record time. That announcement was
made by no other than Tommy Thompson, because of the excitement about
molecularly targeted approaches.
But people ask me, "Well, is this going to work in all cancers? Is Gleevec
going to work in all cancers?" In fact, Gleevec does work in one other
particular type of cancer, called a gastrointestinal stromal tumor. As it
turns out, this particular cancer is driven by a very similar abnormality.
This family of enzymes called tyrosine kinases comprise a family of about
150 different enzymes. When you think about a family, it's as if you went to
a family picnic and there are 150 people there, some of the family members
would look virtually identical; you could hardly tell them apart. Others,
you'd wonder, is that really a family member? Where did they come from?
As it turns out, these tyrosine kinase families are no different. Some of
them look almost identical, and Gleevec inhibits two or three of these
enzymes of this family, but no others. In this gastrointestinal stromal
tumor, one of these other family members causes this cancer and this family
member is also inhibited by Gleevec. And we've seen remarkable success in
this particular tumor. A cancer which had a response rate to chemotherapy of
less than five percent now has a 60 percent response rate. Patients with
massive abdominal tumors are having their tumors shrink, often within days
to weeks.
But the real issue is again; will Gleevec work in all cancers? We've got to
go back to our thermostat. If you think about it, in our thermostat there
could be hundreds of pieces that are broken. If you brought a thermostat to
me and I'd say, "Well, I can replace a part. I don't know if it's broken,
but I could replace the part," you'd say to me, "Well, why don't you figure
out what part's broken, first, before you go replacing anything?"
That's the issue we've got to get at with each and every cancer. In each and
every cancer, there's likely to be a different part that's broken. In each
and every cancer, we've got to figure out what part's broken before we can
fix it.
So as we look to this future, of cancer therapeutics, we've got to determine
what parts are broken. But I think it's also useful, if we think about the
future of cancer therapies, for us to look back and look at some other
analogies.
If you think about where we were in the year 1900, infections were the top
three leading cause of death in this country: pneumonia, tuberculosis, and
enteritis. Cancer showed up as number eight. [In] The year 2000, cancer is
number two, and it's projected that within several years, it's likely to
become number one leading cause of death.
So what happened in the 1900s to make a lot of infections become treatable
or eradicated? There were three major events in the 1900s. One event seems
pretty trivial, but it was actually improved sanitation and refrigeration.
The antibiotic era was born in 1900s. And the other thing that's happened is
vaccinations. Let's recast that slightly. If you think about improved
sanitation or refrigeration, [those are] preventative measures. I also
include early detection in that, as we think about trying to eradicate
cancer. Antibiotics are specific therapies, treatments like STI -571 or
Gleevec. Vaccination is harnessing the power of the immune system.
So when I think ahead to the 21st century, in trying to eradicate cancer and
make cancer a treatable disease, I think we take the same approach:
Preventive strategies, early detection, specific therapy, and harnessing the
power of the immune system. If we can combine those sorts of treatments, if
we can continue to provide the research dollars and the research along all
of those avenues, I think that in the 21st century, we should be able to do
what we did in the 20th century with infections.
As we look to this future, I want to share one last anecdote with you. This
is a patient who was the very first patient treated from Australia. Patients
traveled from around the world as the news of Gleevec was beginning to get
out, and this patient traveled from Australia. She had been on therapy now
for over a year and a half. Last year, she had to reschedule an appointment
because of an extremely important event in her life. As it turns out, she
was selected as one of the Olympic torchbearers that made its way through
Australia on its way to Sydney last year. She called, and she shared this
news with me, and said, "'Dr. Druker, there's no way I could have done this
on the interferon therapy that I was on for my leukemia. If it weren't for
Gleevec, I couldn't have done this.'"
To me, this just symbolizes where we are. It symbolizes to me what we can
accomplish when we understand what causes a particular cancer. But it also
symbolizes to me the great hope we have for the future. If we can do this
for one cancer, we can do it for all cancers.
Thank you very much.