2012 Dickson Prize Winner
Brian J. Druker, MD
Director, Oregon Health & Science University Knight Cancer Institute
JELD-WEN Chair of Leukemia Research
Investigator, Howard Hughes Medical Institute
Brian J. Druker was born and grew up in Minnesota. The youngest of four children, he attended public school in St. Paul, where he excelled in science and math. His father was a chemist who had patented printing processes used by his employer, 3M. It was no surprise, then, that Druker chose to study chemistry when he enrolled at the University of California, San Diego (UCSD). He graduated with a BA in 1977 and stayed on at UCSD for medical school, earning his MD in 1981. He completed a residency in internal medicine at Barnes-Jewish Hospital/Washington University in St. Louis. He then moved to the Dana-Farber Cancer Institute of Harvard Medical School for a fellowship in medical oncology. After the three-year fellowship, Druker remained at Dana-Farber another six years as a Harvard instructor.
At Dana-Farber, Druker studied the processes by which normal cells become malignant. The lab he worked in focused on enzymes that trigger complex cellular pathways; eventually, Druker turned his attention to one enzyme in particular, a tyrosine kinase implicated in chronic myeloid leukemia (CML). This mutated enzyme, called BCR-ABL, triggers the wild proliferation of white blood cells known as leukemia.
In the late 1980s, Druker was among a handful of oncologists who thought that a therapy that disabled the mutant gene without damaging normal cells would represent a dramatic improvement over traditional, highly toxic chemotherapy. Druker and colleagues developed a novel way to measure the activity of the enzyme and, thereby, created a means of measuring the effectiveness of any CML treatment.
In 1993, Druker left Harvard for Oregon Health & Science University. That same year, he initiated discussions with a colleague at a Swiss pharmaceutical firm (which would eventually merge with another to form Novartis) about an experimental compound that had been found to block the activity of enzymes in vitro. When Druker received his first batch of this compound, called CGP57148 (also known as STI571, Gleevec, Glivec, or imatinib mesylate), he poured small amounts of it into trays of white blood cells derived from a CML patient. The abnormal cells not only stopped growing, they died. When he added even larger amounts of the drug to normal white blood cells, they seemed to survive with no damage.
For the next several years, Druker worked with his colleagues at Novartis to develop a version of the drug that could be tested in humans and would prove to be an effective treatment for CML. Many scientists at this time argued that a therapy targeted at a single mutated enzyme was highly unlikely to work without unintended, negative consequences, given the incredible number of enzymes at work in the body.
In 1997, frustrated with the slow pace of the drug’s development, Druker went around Novartis and took his data straight to a toxicologist at the Food and Drug Administration, who indicated that an investigational new drug application based on this data would likely meet with approval. In 1998, the first human trial of imatinib, known as Gleevec, began under Druker’s direction. In late 1999, he announced the initial results of the trial, which showed that all 31 patients in the study had responded to the drug, with 30 achieving normal white blood cell counts within a month. Side effects were deemed mild to moderate.
Imatinib is currently approved for CML, gastrointestinal stromal tumors, and five other cancers. Druker’s role in the development of imatinib and its application in the clinic helped usher in the era of personalized cancer medicine. By demonstrating that it was possible to target a specific mutation causing cancer and shut it down, Gleevec’s success ultimately led to the development of dozens of other FDA-approved targeted therapies and even more that are in clinical trials or about to be approved. The impact of the breakthrough resulted in numerous awards for Druker, including the American Cancer Society Medal of Honor, the Charles F. Kettering Prize from the General Motors Cancer Research Foundation, the Lasker-DeBakey Clinical Medical Research Award, the Japan Prize in Healthcare and Medical Technology, and many other honors. He is a member of the Institute of Medicine, the National Academy of Sciences, and the American Academy of Arts and Sciences.
As director of the Oregon Health & Science University Knight Cancer Institute, Druker is building upon his pioneering research by assembling a team of world-class scientists to, among other things, write the equivalent of an operating manual for cancer. By figuring out how cancer cells function together, researchers will have the knowledge required to develop more drugs to stop it. Druker also is continuing his leukemia research. A current project is aimed at learning why a small percentage of CML patients develop resistance to Gleevec and why most patients on the drug have minute levels of cancer that linger, even after successful treatment. Resistance to Gleevec appears to result from secondary mutations in the BCR-ABL kinase that reactivate signaling and aberrant white blood cell production. Druker and colleagues have developed compounds to inhibit these mutations, and some of these are now in clinical trials with others already FDA-approved. Druker has also turned his attention to other leukemias using the same approach he applied to CML. His laboratory is working to identify the molecular defects that drive the growth of other leukemias and to use this information to develop new, targeted treatments to improve outcomes for patients with these leukemias.