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Brian Druker
(1955 - )
Born in
Year of Discovery: 1996

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Gleevec is Cause for Glee for Leukemia Patients

Cancer doctors witnessed the results with awe and amazement.  Their patients who teetered near death, previously without hope, were leaving the hospital, feeling well, full of new optimism, after being dosed with a new drug.  Gleevec is the “Magic Bullet” drug that attacks only the molecule which causes a form of leukemia (chronic myelogenous leukemia - CML), a ray of hope from teams of scientific minds led by Brian Druker and Nicholas Lydon.

Leukemia is a cancer of the bone marrow that prevents the normal manufacture of the red and white blood cells and platelets.   There are several types.  CML is a type that affects particular kinds of white cells – the myeloid cells. It is caused by the swapping of pieces of DNA between two chromosomes.  This causes a protein to trigger white blood cells to go into a cycle of ceaseless division, hence cancer.  A patient with this kind of leukemia will eventually have extremely high white blood cell counts.  Past treatments were based on killing these cells.  This was attempted by bone marrow transplants or by interferon injections.  The cure rate was about 50%.  Both of these treatments had severe side effects.

Dr. Druker became interested in leukemia in medical school.  He took an elective class which covered the history of chemotherapy.  Fascinated by the story of how another type of leukemia (acute lymphoblastic leukemia – ALL) in children became largely curable using chemotherapy, he thought there had to be a better way to treat leukemia than such harsh treatments. 


Druker took the somewhat unusual path of both treating leukemia patients and also working in the lab to try to find cures. "For me, the connection to cancer patients has been a driving force in my career," he says. "They compelled me to work harder and faster and to be their advocate for new and better therapies."  He works hard at everything he does, even his recreation.  He’s an avid runner and has participated in marathons.

In the 1990s he began looking for the abnormalities in cancer cell growth and specifically at the effect of enzyme inhibitors in animal models of cancer. His work led him to an enzyme that cancer cells seemed addicted to (tyrosine kinase). He thought that inhibiting the enzyme might inhibit the runaway cell growth of the cancer cells.

He then approached Nicholas Lydon, of Ciba-Geigy, a pharmaceutical company. Lydon specialized in tyrosine kinase inhibitors. Working together they were able to identify the drug, Gleevec, as a compound which might kill CML leukemia cells but leave healthy cells alone. After many studies, they convinced the drug company Novartis (which Ciba-Geigy had become after a merger) to put the drug into a human clinical trial. This was not an easy corporate decision. Clinical trials are very expensive, and because CML is a rare disease, it was possible that Gleevec would be unprofitable, even if successful.

Still, Novartis did decide to proceed and in June, 1998, a clinical trial began using the drug.  Within 6 months, a most remarkable thing happened. Most clinical trials of new cancer drugs measure success if the drug extends the life of a small percentage of patients by a few months. For Gleevec, 53 out of 54 patients achieved remission – their white blood cells counts became normal. Plus, there were few side effects!

Given the great results, they expanded the trial.  Knowing that it was working for patients in the chronic or stable phase of the disease, they offered it to patients in “blast crisis,” the name given to the terminal stage of this kind of leukemia. They were stunned. “I'll never forget it,” Charles Sawyers, who worked with Druker, said. “Some of these patients were hospitalized, in wheelchairs, and on oxygen with only weeks or months to live. Within a week or two, they were walking out of the hospital in complete remission.”

Less than 3 years after the first clinical study, the US Food and Drug Administration approved the drug. Now, the five year survival rate for CML patients is 90%.

The most remarkable aspect of the search for a CML cure was that it represented a revolutionary new paradigm in trying to cure cancer. For the first time, Druker’s group showed that a mutated gene that was crucial to the progression of cancer could successfully be targeted by a drug. “To identify the target for Gleevec took 25 years,” Druker says. “We can now compress that into four days! That’s what we are about, accelerating the pace of progress.” Now over 500 molecularly targeted drugs are being developed using this model.

For their work Brian Druker, Nicholas Lydon, and Charles Sawyers are the winners of the 2009 Lasker DeBakey Awards, one of the highest honors in American science.  Brian Druker’s philosophy of medicine can be summed up with the following statement.  "There is no question that we can defeat cancer. What it requires is knowledge. When we understand what is broken, we can fix it!"

 

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Introduction by Martha Pat Kinney



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Table of Contents

Introduction
Key Insight
Key Experiment or Research
Key Contributors
Quotes by the Scientist
Quotes About the Scientist
Anecdotes
Fun Trivia About The Science
The Science Behind the Discovery
Personal Information
Science Discovery Timeline
Recommended Books About the Science
Books by the Scientist
Books About the Scientist
Awards
Major Academic Papers
Curriculum Vitae
Links to Science and Related Information on the Subject
Sources

 








Click the image to view Brian Druker's Lasker Foundation interview
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Image Flow Here




Key Insight




Key Experiments or Research

Chronic Myeloid Leukemia is caused by the swapping of pieces of DNA between two chromosomes.  Specifically, parts of chromosome 9 and 22 trade places.  (A human normally has 46 chromosomes)  This defect is known as the “Philadelphia” chromosome.  This abnormality causes a signal protein to go into a cycle of ceaseless division.  Initially these cells mature and work properly, so there are no serious symptoms.  But eventually, these abnormal cells in the bone marrow become so numerous that they spill out into the regular blood system causing the white blood cell count to become extremely elevated and the types of white cells normally present in the blood to become dominated by these cancer cells.  This is known as a “blast crisis” and can rapidly lead to death.

When Druker began his work, chemotherapy drugs were based on the fact that cancer cells reproduced faster than normal ones.  The problem with this approach was that while it targeted dividing cells, healthy cells also divide and are thereby targeted.  So his approach was different - more specific.

Dr. Druker began his work on oncogenes ( a gene that causes cancer), working with tyrosine kinase, an enzyme that controls cell growth by regulating phosphate groups.  It was thought that this particular enzyme might be the culprit in causing the runaway cell growth.  He developed a reagent (a substance in a test) which identified drugs that inhibit cancer cell growth.  Using that reagent, he began screening drugs provided to him by Lydon, a scientist working for Novartis, and was able to identify the drug, Gleevec as a compound which could kill leukemia (specifically CML) cells but leave healthy cells alone.

Deciding Gleevec was a compound worth testing, he and Lydon approached the drug company, Novartis to put the drug into clinical trial. This was not necessarily an easy decision for Novartis. Clinical trials are very expensive, and because CML is a rare disease, it was possible that Gleevec would be unprofitable, even if successful. Still, Novartis did decide to proceed and in June 1998, a clinical trial began using the drug.  Within 6 months, a most remarkable thing happened. Most clinical trials of new cancer drugs measure success if the drug extends the life of small percentage of patients by few months. For Gleevec, 53 out of 54 patients achieved remission – their white blood cells counts became normal.  Plus, there were only mild side effects!

Given the great results, they expanded the trial.  Knowing that it was working for patients in the chronic or stable phase of the disease, they offered it to patients in “blast crisis.” That is when the most remarkable thing happened.  Patients who were at death’s door, were up and about and leaving the hospital within a week of their first dose. Less than 3 years after the first clinical study, the US Food and Drug Administration approved the drug.

In the  meantime, an international study began comparing the drug with interferon.  After a year and a half, the results were so skewed towards Gleevec that the researchers closed the trial and switched almost all the patients to Gleevec.  Now the overall survival rate for patients 5 years after diagnosis is 90% compared to 50% with previous therapies with far fewer side effects. 

The most remarkable aspect of the search for a CML cure was that it represented a revolutionary new paradigm in trying to cure cancer. For the first time, Druker’s group showed that a mutated gene that was crucial to the progression of cancer could successfully be targeted by a drug. “To identify the target for Gleevec took 25 years,” Druker says. “We can now compress that into four days! That’s what we are about, accelerating the pace of progress.” Now over 500 molecularly targeted drugs are being developed using this model.


Key Contributors

 

The Team
Explore other scientists who furthered this lifesaving advance.
Lifesavers: Leukemia
Nicholas Lydon
Developed Gleevec, a new-generation drug that targeted leukemia's mutated gene.
Charles Sawyers
Developed the next generation drug, Sprycel, for patients who resistant to Gleevec.




Quotes by the Scientist

“The view then was that cancer was far more complicated and people didn’t believe that  targeting a single genetic abnormality would be sufficient. Despite our success in preclinical models, people were doubtful that the drug would reach sufficient concentrations in patient cells and there were concerns about potential toxicity.”

"For me, the connection to cancer patients has been a driving force in my career," Druker says. "They compelled me to work harder and faster and to be their advocate for new and better therapies." 

"There is no question that we can defeat cancer. What it requires is knowledge. When we understand what is broken, we can fix it!"

“To identify the target for Gleevec took 25 years,” Druker says. “We can now compress that into four days! That’s what we are about, accelerating the pace of progress.”



Quotes About the Scientist




Anecdotes




Fun Trivia About the Science




The Science Behind the Discovery



Personal Information

University of California–San Diego: Medical School
Washington University’s Barnes Hospital:  residency
Howard Hughes Medical Institute (HHMI): Investigator
Oregon Health & Science University (OHSU): director of the OHSU Knight Cancer Institute



Scientific Discovery Timeline




Recommended Books About the Science




Books by the Scientist




Books About the Scientist

 



Awards

2009 Lasker DeBakey Clinical Medical Research Award

Lasker Foundation Press Release of Award

Lasker Foundation Award Article



Major Academic Papers Written by the Scientist



Curriculum Vitae



Links to Information on the Science

See a patient’s video on Oregon Health and Science University’s site. It also has articles, videos, and links.

Journal of Clinical Investigation has an excellent in-depth article that also has personality anecdotes.

Awardee Profile by Burroughs Wellcome Fund

Lasker Foundation Press Release of Award

Lasker Foundation Award Article

Howard Hughes Medical Institute Article

Smithsonian Article



Sources/References