reprinted from Issue 16, Spring 2013 of Frontiers of Medicine (PDF)
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My role as a physician-scientist is not just to publish another paper and move on to the next project," says Charles Sawyers, MD, chair of Memorial Sloan-Kettering Cancer Center’s Human Oncology and Pathogenesis Program. "If you really believe your data, you should push it forward into the clinic."
Sawyers has used this approach to revolutionize the treatment of chronic myeloid leukemia (CML) and prostate cancer, studying the genetic makeup of these diseases to develop new therapeutics.
He began his residency at UCSF in 1985, and vividly remembers caring for leukemia patients during month-long hospitalizations for bone marrow transplants. "You see the same patients every day and form a pretty intense relationship," says Sawyers. "I took care of young adults – some were cured, and some died, right there in front of you. It was very moving."
He gained his first research experience in the lab of physician-scientist Joel Ernst, MD. Ernst also directed him to Owen Witte, MD, a leading UCLA cancer researcher with whom Sawyers later worked as a postdoctoral fellow.
"In an outstanding group of interns and residents, Charles stood out for his compassion, thoroughness, and dedication to ensuring that all his patients got the best care," says Ernst, now on the NYU faculty. "In the laboratory, Charles was as exceptional as he was on the wards – he quickly took to the tools and concepts of molecular biology, and it was clear that he would go far. Even with those expectations, Charles’ accomplish- ments have surpassed anyone’s wildest dreams."
As a trainee and then a faculty member at UCLA, Sawyers cared for leukemia patients while relentlessly pursuing how a mutated gene called BCR-ABL caused CML. "The questions in the clinic were the same things we were working on in the lab," says Sawyers. "People tell you that it’s impossible to do both, but there are ways to align them so it’s not only possible, but synergistic."
He collaborated with Brian Druker, MD, at Oregon Health & Science University, to conduct a clinical trial of Gleevec, a drug that inhibited BCR- ABL in laboratory models. Amazingly, within a week or two, some patients near death walked out of the hospital in complete remission.
"That was an incredibly important experience," recalls Sawyers, saying it inspired a lifelong focus on translating laboratory discoveries into treatments. "I thought, ‘I’ve got the medical and science training. If I don’t do it, who else will?’ That became the driving motivation of my lab."
Unfortunately, patients developed resistance to Gleevec and relapsed. Sawyers and his group discovered a large number of mutations that caused resistance. "This resulted in a period of despair," says Sawyers. "We thought, oh my God, we’ll need 50 drugs to treat this disease!"
Cornering a Shape-Shifter
Then Sawyers began collaborating with John Kuriyan, PhD, at UC Berkeley, an expert in three-dimensional structures of proteins. They found that all the mutations changed the shape of the protein produced by the BCR-ABL gene so that Gleevec could no longer bind to it effectively. But most of these new shapes shared a common feature that might be targeted with another drug.
Sawyers discussed these findings at a scientific meeting, describing what kind of drug might block the protein in this alternate shape. A Bristol-Myers Squibb scientist said one of their drugs, dasatinib, might be a match. Sawyers tested the compound in the lab, then conducted a highly successful clinical trial.
"Gleevec and dasatinib have completely changed the way [CML] is managed, and it was all driven by science," says Sawyers. "Patients I’d known for years who carried a death sentence had a complete change in their outcome. That has been incredibly satisfying."
Sawyers also studies prostate cancer that develops resistance to hormone therapy. "This time, no one called me and said, ‘I have the drug,’ so we had to make it," says Sawyers. He partnered with Michael Jung, PhD, an academic chemist at UCLA, to develop enzalutamide. It won FDA approval in 2012 after a clinical trial showed it significantly increased survival in men with advanced disease.
Sawyers moved to Memorial Sloan- Kettering Cancer Center in New York in 2006, where he continues his research. He was recently appointed by President Obama to the National Cancer Advisory Board, and is president-elect of the American Association for Cancer Research. He is a Howard Hughes Medical Institute investigator, a member of the National Academy of Sciences and the Institute of Medicine, and has received numerous awards, including the Lasker–DeBakey Clinical Medical Research Award.