Re: Talk by Drian Druker - An Oldie but a Goodie

[Guest guest]

Hi Zavie,

Thank you for sharing Dr. Druker's talk with us. I have never seen

that one before.

I'm looking forward to meeting him with my appointment next month!

Sincerely,

Lynn

>

> 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.

>