COMMEMORATIVE LECTURE

Imatinib (Gleevec®) as a Paradigm ofTargeted Cancer Therapies
Brian Druker

Department of Medicine, Oregon Health & Science University, Oregon, USA(Received for publication on May 30, 2008)

Keywords: leukemia, imanitib, molecularly targeted therapy, CML
It is a great privilege for me to be honored with anaward from Keio University. I would especially like tothank the members of the award committee and mynominators for this prestigious award. Cancer is currently the number one cause of death in Japan with morethan twice as many people dying from cancer than fromany other cause. But as you will hear from my comments
today, I am incredibly optimistic about our ability to impact cancer. To fully understand my optimism about thefuture of cancer research, I need to take you back 100years, so that you can see the parallels to today.
In 1900, Japanese society was benefiting from andleading the industrial revolution. With jobs being in thecities, instead of in agriculture, people moved in large
numbers to the cities. In 1900, Tokyo was the fifth largest city in the world with a population of nearly 2 million
people. But, Tokyo had many problems. There was massive overcrowding. There was no running water, no sewage system, and infectious diseases were rampant. In Japan the life expectancy in 1900 was 43 years. If you had
a child, they had a 1 in 10 chance of dying before age 4.
Pneumonia, tuberculosis, and diarrheal diseases likecholera were the top 3 causes of death, accounting for
30% of all deaths. As late as 1914, there were outbreaksof typhoid fever.
If you went to the doctor, this is what your encountermight be like.

Many.”
Patient: “Will I get well?”Dr. Ehrlich: “You must come here twice weekly forsweat baths, observation, and medical supplies. The
treatment consists largely in rubbing yourself with thisointment.”
Patient: “Tell me doctor, will I get well?”Dr. Ehrlich: “Rub a different part of the skin every nightof the week so that no part of the skin is rubbed morethan once weekly.”
Patient: “There is a girl in Munich with whom I am inlove…who loves me. We had planned to be married assoon as I graduate. Tell me doctor. Tell me the truth. Can
we ever get married…now?”Dr. Ehrlich: “I’m afraid marriage is out of the question
now, sir…. You may dress now.”
Patient: “Does anybody ever get cured?”
Dr. Ehrlich: “Of course. There have been many cures…
many.”
Of course, “Many cures,” I’m afraid, was false hope.
Despite the bleak picture, scientists and politicians of
the day were incredibly optimistic and were predictingthat infections would soon be treatable or eradicated.
What led to this optimism was the establishment of thegerm theory of disease that held that infectious agents,
not mythical forces, caused diseases. The pioneers of thelate 1800s and early 1900s had identified the bacteriathat caused tuberculosis, and many other bacteriae thatcaused infections were being identified. Another pioneer,
Louis Pastuer, had introduced a vaccine for rabies. Therewas real cause for optimism as is captured in this next
video.

Video 1.
Voice: “Next.”
Dr. Ehrlich: “What you have is a contagious disease, aninfection just like any others. I have seen cases where it
was transmitted by an inanimate object…. You musn’t
be disheartened. There are many as badly off as you.

Dr. Druker is the recipient of the 2007 Keio Medical Science Prize.
Presented at the Keio Medical Science Prize Commemorative Symposium, December 5, 2007.
Reprint requests to: Dr. Brian Druker, Department of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, L592, Portland, Oregon 97239, USA1

2Video 2.
Paper on Desk: “Cause of Syphilis Discovered.”
Dr. Ehrlich: “[Names], everybody, come here!”
Student #1: “Professor, you called?”
Dr. Ehrlich: “Gentleman, it would seem that the germof syphilis has been discovered.”Student #1: “Really?”
Student #2: “By whom?”Dr. Ehrlich: “By one Fritz Schaudinn. The German
Medical Weekly sent me these proofs for approval. Listen, ‘The spirochete pallidum is a protozoan. It is a fine,steeply convoluted filament with 6-14 turns.’ It is decidedly motile, with forward, turning, and bending movements. Tell me, does that description put your mind toanything else? It is decidedly motile, with forward, turning, and bending movements.”
Student #3: “Why that’s just like the Tyrpanosoma.”
Dr. Ehrlich: “Right.”
Student #2: “If the germ has been discovered, there’s
cause to hope for a cure.”
Dr. Ehrlich: “Yes, there is hope.”That’s precisely the point. If you understand the cause,
there is hope for a cure.
The scientific breakthroughs of the 1900s translated
into enormous gains against infections. In the early
1900s, public health measures such as chlorination ofwater, pasteurization of milk, improved sanitation andrefrigeration made our food and water supplies safe.
Antibiotics, not even conceived of in 1900, were introduced in the late 1930s. Penicillin was first used in 1942.
In one of the first descriptions of the use of penicillin, a33 year old woman was hospitalized with a life-threatening pneumonia. She was delirious and her temperaturereached 107 ˚F. Treatment of the day consisted of surgery, sulfa drugs, blood transfusions, and they had no effect. As a last resort, her doctors injected her with a tiny
amount of an obscure, experimental drug called penicillin. Overnight, her temperature dropped to normal andthe next day, she was no longer delirious. She survived
to marry, raise a family, and one day, met Sir Alexander
Fleming, the discoverer of penicillin. These were magicbullets for treating infections, the likes of which had
never been seen before. Physicians were amazed bythese drugs as disease after disease fell to these agents.
The other major advance in the 1900s was the introduction of vaccines. I suspect that many of you can remember the polio epidemic of the 1950s. Hospital ward
after hospital ward filled with iron lungs. In 1952 alone,
there were 10,000 cases of polio reported in Japan. In
1955, the Salk polio vaccine was introduced and by
1965, there were only 50 cases of polio in Japan. Diseases like smallpox have been eradicated with vaccination.
Mumps, measles, rubella, the diseases that we all grewup with, are now memories.
In the year 2007, we face new challenges. Cancer isDruker B: Imanitib as a Paradigm of Targeted Cancer Therapies

now the leading cause of death in this country. Hopelessencounters between doctors and cancer patients, like theone from the movie clip, are common.
But scientists of today are as optimistic as our counterparts were 100 years ago. That is because in the last decades of the 20th century, cancer researchers establishedthe gene theory of cancer. That is, genes in our cells thatlead to cancer have been identified. And like a century
ago, where the hope was that this understanding would
lead to effective treatments, this is our hope for cancer.
But we have more than hope. We have proof withGleevec® that tells us that by understanding cancer, wecan develop effective treatments. Over the past three decades, cancer researchers have identified the precise abnormality that causes the white blood cells to grow uncontrollably in a particular form of leukemia called
chronic myelogenous leukemia. This leukemia accounts
for 20% of all leukemias and is characterized by a whiteblood cell count that is up to 50 times higher than normal. In collaboration with Novartis Pharmaceuticals, mylaboratory developed Gleevec®, a drug that completely
shuts down the specific abnormality that drives the uncontrolled growth of white blood cells in this disease. Inclinical trials, virtually all of our patients have had theirblood counts return to normal, and in up to three quartersof our patients, we can no longer detect leukemia cells intheir bone marrow. Remarkably, this once-a-day pill has
been well tolerated, with minimal side effects. In short, it
is a simple, effective treatment that disables the cancer
without disabling the patient. Gleevec® is now in use
worldwide and today, well over 100,000 patients havebeen treated. Now, the five year survival is 95% for thispreviously fatal leukemia. People diagnosed with thisleukemia were once told they had 3-5 years to live; now
they are projected to live 30 years.
Let me give you an example of a patient who has been
helped dramatically by Gleevec®. LaDonna, a retired dietician first came to see me in December of 1999. Her
spleen, which should normally be the size of my fist, wasas big as a watermelon and pressing on her stomach sothat she was barely able to eat, and she was losing weightat the rate of 3-4 pounds per week. LaDonna knew she
was dying and that her time was short, maybe onlyweeks. She had picked out a burial plot and was deciding
on the music she wanted played at her funeral. Within aweek of starting Gleevec®, her spleen began to shrink
and within a month she was restored to normal health.
Today, I can no longer detect traces of her leukemia. LaDonna is now spending her time playing with her grandchildren, pictured here, including one she wasn’t supposed to meet, a grandson named Will, who was named
for her will to live.
Gleevec® has shown cancer doctors that we can develop medicines that are like magic bullets that work quickly and effectively on patients for whom there previously
was no hope. Targeted therapies like Gleevec® are now

Keio J Med 2010; 59 (1): 1－3

part of the mainstream. There are now over 100 targetedcancer therapies in clinical trials and over 200 in development. Every drug company’s cancer pipeline has
moved from chemotherapy drugs to targeted agents.
But just like penicillin does not cure all infections,Gleevec® will not work against all cancers. Think of thisas a thermostat that perfectly regulates the temperature
between 68 and 72 degrees. If the temperature falls below 68 the thermostat turns on and when the temperaturereaches 72, it shuts off. Perfect temperature control. Just
like this thermostat, our bodies regulate the numbers ofcells that are produced every day, making just enough toreplace daily losses. Now imagine the thermostat is broken and is stuck on. The temperature climbs, 72, 80, 90
and higher. Or in the case of cancer, the cells keep growing and growing, forming a tumor. The problem is figuring out what part has broken. Sure, we could replace thethermostat which would be expensive and may not work
quite as well. Or in the case of chemotherapy, we could
hit the thermostat with a hammer and hope that fixes theproblem, but certainly leaves it battered or broken. Now
imagine if we could take the thermostat apart, piece bypiece, figure out how each part works and just replace
the broken part. That’s exactly what we did withGleevec®. But our thermostat has hundreds of parts that3

can break, and to develop more treatments like Gleevec®,
we need to figure out what part has broken in each andevery cancer. With this understanding there will be evenmore hope for cures.
But just like antibiotics are not the only treatment for
infections, we need to take a broad-based approach totreat cancer. We certainly need more drugs like Gleevec®,
but we also need a better understanding of the power ofthe immune system so that we can harness it to attack
cancer. In addition, we need a better understanding ofwhat places us at risk of developing cancer so that wecan develop strategies to prevent cancer or diagnose cancer at its earliest, most treatable stages. This is exactly
what Japan has done with their efforts to identify stomach cancer at its earliest stages. These efforts have resulted in an enormous decrease in the death rate fromstomach cancer in this country and I congratulate you.
I firmly believe that we have the technology in hand tosolve the cancer problem and I hope that I have given
you a sense of why I am so optimistic about the future.
My hope for the future is that someday soon, we will
think of cancer in much the same way we think of infections. Then, pictures like these, filled with survivors, will
become the norm.
Thank you very much.