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(1959 - )
Year of Discovery: 2001
For Relapsing Leukemia Patients, In Stepped Sawyers
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 the molecule inside a cell which causes a form of leukemia (chronic myelogenous leukemia - CML). But for 10-15% of unlucky patients, they relapsed and the cancer returned. In stepped Charles Sawyers. He had helped design the clinical trial of Gleevec, and now turned to research a solution for the relapsing patients.
Dr. Sawyers first became interested in leukemia during his internship. “During my internship, I was greatly affected by the time I served on the leukemia ward. It was the first time I took care of patients my age. Leukemia treatment is very intensive. Patients spent a month in the hospital, and you get to know them well. Based on that experience, I decided to work on leukemia.”
In the 1990s he began collaborating with Dr. Brian Druker who had developed a leukemia drug, Gleevec. He helped design the clinical trial for the drug. Gleevec was a new way to attack cancer. It targeted the signal protein inside the cell causing the abnormality, instead of just trying to kill the overabundant number of white blood cells. The results were stunning! Within 6 months, almost every patient had achieved a remission (their white blood counts were normal). Looking back, Dr. Sawyers commented, “It was a transforming experience to participate in something that played out exactly as the work in the laboratory would have predicted. It created in my mind a sense of urgency that there are things that we know now that could really change patient care.”
While the results were wonderful, over time some patients lost their response to the drug. “After seeing such a great turnaround in blast crisis patients with full-blown leukemia, the shock of seeing them develop resistance was an emotional rollercoaster for both patients and physicians. We knew that single target drugs really don’t cure cancer and that eventually there was going to be a dark cloud in an otherwise beautiful story. But it was really rough,” Sawyers remembers.
Rather than despair, Sawyers tried to find out why some patients relapsed. He began working with structural biologist, John Kuriyan. They came to a deeper understanding of the mutations or gene expressions that caused the cancer cells. Sawyers’ group then came up with the drug, Sprycel. Approved in 2006, it has been effective against all but one commonly occurring mutation. Sawyers thinks that ultimately, physicians will be able to offer their patients a “cocktail” of inhibitors that work against all common mutations of the enzyme, so drug resistance would be less likely to happen.
For his work he has been awarded the 2009 Lasker-DeBakey Award. He shares the prize with Brian Druker and Nicholas Lydon, the two scientists who developed Gleevec. These drugs have taken a disease that was a death sentence for many and turned it into a manageable “condition.” He is optimistic about the future stating that, “We live in a unique time where you can just taste how molecular understanding in the lab is applicable to things in the clinic.”
Introduction by Martha Pat Kinney
Table of ContentsIntroduction
Key Experiment or Research
Quotes by the Scientist
Quotes About the Scientist
Fun Trivia About The Science
The Science Behind the Discovery
Science Discovery Timeline
Recommended Books About the Science
Books by the Scientist
Books About the Scientist
Major Academic Papers
Links to Science and Related Information on the Subject
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While Gleevec seemed to alleviate this problem, another problem soon surfaced. Some patients developed resistance to the drug and the doctors and scientists were not sure why. Sawyers began assessing the enzyme activity from patients over the course of their treatment. He discovered that in patients who relapsed, Gleevec was no longer inhibiting the enzyme activity. The enzyme had changed during the course of their therapy.
In the analysis of the faulty gene, Sawyers found that one amino acid had replaced another at one particular spot in the protein. Structural biologist, John Kuriyan (University of California, Berkeley) was able to substantiate Sawyers observations using x-ray crystallography. This simple change of amino acids left a large hole in the spot where Gleevec normally attached to the enzyme so the drug wouldn’t attach and work. He did more studies and found more than 50 genetic deviations that could cause the drug to have no place to attach to the enzyme.
He also found that the drug only bound to the enzyme when it was in its inactive form. So he set out to find an agent that blocked the resistant enzyme’s activity when it was in its active form. He worked with scientists at Bristol-Myers Squibb to create a drug called Sprycel. It did what he wanted – it bound to the enzyme in its active form. The drug rapidly went through clinical trials and was approved by the Food & Drug Administration for use in patients who had become resistant to Gleevec.
“During my internship, I was greatly affected by the time I served on the leukemia ward. It was the first time I took care of patients my age. Leukemia treatment is very intensive. Patients spent a month in the hospital, and you get to know them well. Based on that experience, I decided to work on leukemia.”
“It was a transforming experience to participate in something that played out exactly as the work in the laboratory would have predicted. It created in my mind a sense of urgency that there are things that we know now that could really change patient care.”
“We live in a unique time where you can just taste how molecular understanding in the lab is applicable to things in the clinic.”
“After seeing such a great turnaround in blast crisis patients with full-blown leukemia, the shock of seeing them develop resistance was an emotional rollercoaster for both patients and physicians. We knew that single target drugs really don’t cure cancer and that eventually there was going to be a dark cloud in an otherwise beautiful story. But it was really rough.”
The Science Behind the Discovery
Johns Hopkins University - medical school - M.D.
Memorial Sloan-Kettering Cancer Center: Head of the Human Oncology and Pathogenesis Program (HOPP)
Lasker Foundation Press Release of Award
Lasker Foundation Award Article
Links to Information on the Science
Memorial Sloan-Kettering Cancer Center Interview with Charles Sawyers
Journal of Clinical Investigation’s excellent in-depth article that includes some personal facts.
Howard Hughes Medical Institute’s Article
Memorial Sloan-Kettering Cancer Center Article