PALO ALTO, CA—In the late 1970s, Brian J. Druker, MD, was a first-year medical student and was taking a class on the history of cancer chemotherapy, which traced a number of chemotherapy drugs through the cure of childhood leukemia. While fascinated by the course, Druker wrote in his notebook about how there was a lack of understanding of the differential effects of these drugs and that only when the biochemical basis of those differential effects was understood could the field be advanced.
After his medical residency, Druker ended up in the lab of Tom Roberts at Dana-Farber Cancer Institute, Harvard Medical School, in 1985, studying signal transduction in kinases. In 1986, monoclonal antibody pioneer Deborah Morrison joined the lab and began to study the RAF kinase, and when Roberts was looking for a volunteer to work with Morrison, who is now the Chief of the Laboratory of Cell and Developmental Signaling at the National Cancer Institute, to make an anti-phosphotyrosine antibody, Druker jumped in.
“I figured, ‘What could be so hard about making an antibody, and I’ll learn a useful skill,’” Druker told a standing-room-only crowd in Berg Hall at Stanford’s Li Ka Shing Center (LKSC) Conference Center during his acceptance speech for the Lifetime Achievement Award at the 2023 Stanford Drug Discovery Symposium. “Two years later, and about six to eight fusions later, we had the phosphotyrosine antibody, 4G10, which became one of the largest selling phosphotyrosine antibodies in the world.”
More importantly, 4G10 allowed Druker to collaborate with any number of individuals to help identify tyrosine-phosphorylated proteins. However, at the time, kinases weren’t a viable drug target. The general consensus was that developing a competitive inhibitor of ATP wouldn’t work because it would shut down every single kinase, which led Druker to the question of specificity and, eventually, two researchers, Jürg Zimmermann and Nicholas Lydon, from Ciba-Geigy (which later became Novartis), one of the few pharmaceutical firms in which scientists were conducting tyrosine kinase inhibitor research.
Druker believed that the first disease that would fall under targeted therapy was chronic myeloid leukemia (CML) because every single patient with the disease had the BCR/ABL tyrosine kinase mutation. In animal models, the mutation caused disease, and when knocked out, the kinase no longer functioned and cancer cell proliferation ceased.
But as Druker began setting up in vitro and in vivo models to study BCR-ABL, by a twist of fate in 1990, Sandoz made a hundred-million-dollar agreement with Dana Farber for exclusivity in the field of signal transduction, which no longer allowed Druker to work with Ciba-Geigy. So, in 1993, Druker left Dana Farber, moved to OHSU, and immediately called Lydon to ask if he had any ABL inhibitors. “Within six weeks of arriving in Oregon, I had compounds in my lab, and one of them was ST1571,” said Druker. “We then published preclinical data on ST1571 or Imatinib, which was later renamed Gleevec. It was a strong inhibitor of ABL and a selective killer of ABL-expressing cells in vitro and in vivo. Zimmerman was able to make this into a highly bioavailable, or oral, formulation.”
In another twist of fate, in 1996, Ciba and Sandoz merged to form Novartis. “At a time when there were still concerns about this being a viable target back in the early 1990s, my colleagues were still a pretty pessimistic bunch,” said Druker. “The view was, even though you had some specificity, there’s still going to be toxicity. But the biggest problem was that with 5,000 new patients a year in the United States, the market projected that this would never make enough money to justify its development. But fortunately, we had champions within the company.”
A scientist by the name of Alex Matter was able to convince the group to go forward with a limited-scale Phase I trial, which began in 1998. “It was a unique trial in that, having lived through the development of nonspecific chemotherapy drugs, in a Phase I trial you’d tell a patient that we had no idea what disease this was going to work for, but it might work for your cancer—are you willing to at least give this a try and help out future generations of patients with this drug?” said Druker. “If it was going to work, it was only going to work in CML. As a physician, I couldn’t justify having that talk with a patient where I felt it would have virtually no chance of working.”
Druker was able to convince Novartis to only enroll patients with CML for two reasons. First, it would allow the safety evaluation, and second, it might allow some early readouts on the clinical benefits. “We were absolutely right!” said Druker. “Within six months, we reached 300 milligrams a day and were seeing significant therapeutic benefits, with 53 out of 54 patients responding. The one patient who didn’t respond actually added withdrawal because of some symptoms that are unrelated to the drug. Otherwise, it would’ve been 100%, but with 98% response rates, good durability, and minimal side effects, the drug was rushed through the FDA in record time, in two and a half years after the initiation of clinical trials.”
The FDA’s approval of Gleevec made a major splash nationally and internationally, appearing on the cover of Time Magazine. “If you fast forward through the almost 20 years that [Gleevec] has been on the market, the mortality rate from CML has plummeted,” said Druker. “If you look at Sweden’s registry data, the data there shows that patients diagnosed with CML are expected to live a normal lifespan as compared to age-matched controls.”
Druker admits that Gleevec is not perfect and that there are relapses or resistance, which has spurred drug development. Now, there are six FDA-approved ABL inhibitors that cover a different spectrum of kinase mutations, but all the common mutations are covered by at least one drug. In addition, it spurred the development of many kinase inhibitors—72 FDA-approved and many more in clinical trials. Gleevec helped usher in the era of precision medicine and also demonstrated to the pharmaceutical industry that you could develop drugs for relatively rare diseases and make them quite profitable.
Since his foundational work with Gleevec, Druker has put together a program with support from the Leukemia and Lymphoma Society to try acute myeloid leukemia (AML) and has collaborated to develop some early cancer detection tests with international alliances that include Cancer Research U.K. and industry partners, such as GRAIL. Druker takes pride in becoming one of the top patient accruers. “We’ve understood how to reach out to our communities across the state of Oregon, how to reach into our primary care network, and how to engender trust in what we’re doing with our science among general participants from rural frontiers and a variety of ethnic backgrounds in these innovative studies.”
While all the data he has produced is impressive, the aspect that is most inspiring to Druker is the effect Gleevec has had on people. Druker’s passion for his work comes through as he recounts the stories of some of his patients.
He tells the story of a six-year-old girl, Katie, diagnosed with CML one month after the FDA’s approval of Gleevec, who started on the medication and grew up without having to go through the years of chemotherapy or bone marrow transplants. She ended up going to nursing school, became a nurse at a children’s hospital, has a three-year-old child, and has been off Gleevec for years. Druker recounts the story of a CML patient who traveled from Italy to be treated with Gleevec and whose first words out of his mouth when they met were, “I just want to live long enough to walk my daughter down the aisle.” Not only did the Italian patient do that, but now he’s a proud grandfather.
He has another story about a young man born in a refugee camp who was diagnosed with CML in dental school almost 15 years ago, and now he has a successful dental practice, is married, has a child, and this past November he was elected to serve in the Oregon State House of Representatives. Then there’s a story about the first patient treated in Australia who became one of the torchbearers for the 2000 Sydney Olympics.
“All these are individuals, but pretty soon, one at a time, it adds up to large groups of people thriving and surviving despite a diagnosis of cancer,” said Druker.
