The Evolution of a Lifesaving Drug: A Scientist Reflects

Pictured: Charles Sawyers

Physician-scientist Charles Sawyers

Starting in the mid-1990s, while he was at the University of California, Los Angeles, Memorial Sloan Kettering physician-scientist Charles Sawyers played a pivotal role in the development of imatinib (Gleevec®), one of the first successful targeted drugs for cancer. Gleevec was originally developed for the treatment of chronic myeloid leukemia (CML) and is now used to treat a number of cancer types.

Dr. Sawyers joined MSK in 2006 as the inaugural Chair of our Human Oncology and Pathogenesis Program. His laboratory focuses on developing new targeted therapies for advanced prostate cancer and leukemia.

We asked Dr. Sawyers about the moment he knew that Gleevec was going to be a game changer in the treatment of CML.

When I was in medical school, I became captivated by the potential advances that molecular biology could bring to medicine, especially cancer medicine. At that time in the early 1980s, there weren’t many concrete examples of what was possible, but to me it seemed like the next great thing.

During my medical internship, I was greatly affected by the time I served on the leukemia ward.

I became captivated by the potential advances that molecular biology could bring to medicine.
Charles Sawyers MSK physician-scientist

It was the first time I took care of patients my age. Leukemia treatment was very intensive. Patients spent a month in the hospital, and you got to know them well. Based on that experience, I decided to focus on leukemia research.

In 1996, I became involved in the initial testing of a drug for the treatment of CML, which eventually was named Gleevec. CML is unique in that it is caused by a single mutant protein, called BCR-ABL.

Gleevec is a pill taken once a day with few side effects. It worked so well so early in the trial that it was obvious to all of us involved that it had to be moved forward as quickly as possible. The clinical impact was so dramatic that we became evangelists, trying to get the resources to speed up the clinical testing. Not only did we see almost instant improvement in patients with early-stage CML, we also saw dramatic results in patients who were in blast crisis, the most advanced stage of the disease.

I’ll never forget it. 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.

But the sad part was that these sicker patients who underwent the most dramatic recoveries were the first to develop resistance to the drug, and they relapsed quickly. We set out to solve the puzzle of why patients were developing resistance, which is really the Achilles’ heel of targeted therapy.

The clinical impact was so dramatic that we became evangelists.
Charles Sawyers

We learned that in most patients, an additional mutation was occurring in the BCR-ABL protein, causing it to change its shape and preventing the drug from working. Soon after that we got a call about another drug — which became known as dasatinib (Sprycel®) — that inhibited BCR-ABL in its other shape.

Clinical trials with dasatinib began very quickly, but this time we changed the way we conducted them. We did genetic studies on every patient to give us additional insight into what mutations each patient had. Today when we treat CML, we can use these gene-based measurements to instruct us about which drug to use and to predict how each patient will do.

This genetic analysis of patients’ tumors has become a part of standard care for MSK patients with many different types of cancer. It helps guide the development of new therapies and is the cornerstone for what’s now being called precision medicine.

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