Talk by Drian Druker - An Oldie but a Goodie

[Guest guest]

For all the newbies on this list. Us oldtimers have seen this before, and is

worth a reread.

Zavie

Dr. 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, Nowell and

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. [] Bishop and [Harold]

Varmus, Dr. [] 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 , 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.