Making Oncology History: Imatinib Pioneer Created His Own Opportunities

Brian J. Druker, MD

There are lessons to be learned from interacting with cancer patients, and⎯luckily for the oncology community⎯Brian J. Druker almost missed the most important one.

“If you take care of cancer patients, what you should learn is that you need to make the most out of every day, to live life to its fullest,” said Druker, MD, director of the Knight Cancer Institute at Oregon Health & Science University (OHSU) in Portland. “If I developed cancer and all I did was work hard, that doesn’t seem like a very fulfilling life.”

During the early years of his career, though, it never occurred to Druker to adopt that perspective. Instead, the endless frustration of treating patients he couldn’t cure—or sometimes even help— drove the physician into the lab to work tirelessly at developing new therapies.

As it turned out, it was fortunate for the oncology community that he did. A dozen years ago, Druker’s efforts led to the development of imatinib (Gleevec), an oral tyrosine kinase inhibitor (TKI) initially indicated for patients with chronic myeloid leukemia (CML) that has proved to be one of the earliest and most successful targeted therapies in the oncology armamentarium.

In one trial that helped pave the way for the drug, Druker and colleagues found that imatinib restored normal blood counts in 53 out of 54 interferon-resistant CML patients, a response rate rarely seen in cancer with a single agent (N Engl J Med. 2001;344[14]:1031-1037). Fifty-one of the patients were still doing well after a year on the medicine, and most reported few side effects, according to the National Cancer Institute (NCI) (http://goo.gl/RmIH5).

Imatinib was groundbreaking not just because of those results, but also because of how it generated them. While previously approved molecular-targeting drugs interfered with proteins associated with cancers, imatinib was the first to directly turn off the signal of a protein known to cause a cancer, according to the NCI. The drug was approved in May 2001, with phase II trials still in progress and after an FDA review of less than three months, still an all-time speed record.

Today, patients with CML who take imatinib are projected to survive an average of 30 years, Druker said, a far cry from the three- to five-year prognosis that was standard when he began practicing medicine in the 1980s. And, imatinib has been approved for the treatment of additional tumor types, including Philadelphia chromosome-positive acute lymphoblastic leukemia and KIT (CD117)-positive gastrointestinal stromal tumors.

On a broader scope, the insights that led to the development of the drug have helped lay the groundwork for the creation, by other labs, of several approved treatments for imatinib-resistant CML, and also of targeted therapies for other cancers, including the kinase inhibitors vemurafenib, erlotinib, gefitinib, and crizotinib.

All those developments make Druker glad that he gave the decade of his life from his mid-30s to his mid-40s almost exclusively to research, living a solitary life and working 16-hour days.

Continuing the Fight

“Because of what I did and the sacrifices I made,” the 57-year-old said, “I got to see patients who benefited from a treatment I helped develop, and got to give them hope when they had no hope. That’s a gift that can’t be replaced by anything else.”In the years since imatinib’s approval, Druker has maintained his focus on finding new and better treatments for CML and other leukemias. In particular, he’s seeking ways to beat the resistance to imatinib that arises in about 15% of patients with CML within five years of beginning treatment.

While there are already three TKIs on the market for refractory CML, including bosutinib (Bosulif), approved this fall, “there’s still one mutation that none of those drugs will shut down—T315I,” Druker said.

“We worked for close to six years testing drugs that Ariad designed until we identified one that shut this down,” said Druker, referring to the Cambridge, Massachusetts, pharmaceutical company. “The drug, ponatinib, works incredibly well against that mutation and also across the board in CML, and has made it through clinical trials.” In December, the FDA approved ponatinib, three months ahead of schedule Find out more.

Druker spends a fair amount of time conducting such research in his 16-person lab at OHSU, a hilltop institution that overlooks downtown Portland.

The bulk of his remaining time is eaten up by his “main job” as the “face of the cancer center,” which involves “setting the strategic vision, recruiting faculty, engaging in philanthropy, and forging relationships with our industry partners—biotechs, software and hardware vendors, equipment companies, anyone who helps us do the work.”

Druker also spends one day a week treating patients, teaches several classes a year, occasionally runs a clinical trial, and dedicates a day or two each month to lecturing around the world.

But despite all he does, and his commitment to it, Druker has established at least some of the balance he lacked when imatinib was at the center of his life.

Brian J. Druker, MD . . .

• Has enjoyed reading the Harry Potter book series, by J.K. Rowling, to his three children, starting when each was in first grade. “I enjoyed the fact that there was a plot, character development, and some excitement,” Druker said. “It was a fabulous bonding experience with my children, and it helped them to read and learn.”
• Lives by the motto “Hard work beats talent when talent doesn’t work hard.” This pearl of wisdom from Kevin Durant, of the Oklahoma City Thunder basketball team, stresses a principle Druker learned as he developed imatinib for the treatment of chronic myeloid leukemia: Having a strong work ethic contributes to success.
• Recalls a position as a Little League umpire as his worst job ever. He took the job during college to make some extra money, and quickly learned that “umpires are always on the losing side, particularly with parents. We always got yelled at, which wasn’t fun.”
• Gets his daily exercise by running back and forth to work, a route that totals two miles each way.
• Specialized in oncology because “it seemed there were going to be opportunities in my lifetime to make a difference.”
• Believes the oncology community is on the cusp of a new era of discovery. “A decade ago, all the drug companies were making chemotherapy drugs and had very few targeted drugs and few targets,” he said. “Like big cruise ships, they’re slow; it takes them time to restock their pipelines and generate new drugs, so it can be six to 10 years before you see a new paradigm emerging. That’s about the time it’s taken for these companies to move to targeted therapies, but now they are all in that arena.”
• Participates in an extensive number of professional committees, including membership on the National Cancer Institute Board of Scientific Advisors, the Stand Up To Cancer Scientific Advisory Committee, and the American Society of Clinical Oncology’s Adult Leukemia and Lymphoma Program Committee.
• Has received some of his field’s top awards, including the Lasker-DeBakey Clinical Medical Research Award, the Japan Prize in Healthcare and Medical Technology, and the Meyenberg Prize. “Some of my first awards, like the American Association of Cancer Research’s Richard and Hinda Rosenthal Memorial Award, and the David A. Karnofsky Memorial Award from the American Society of Clinical Oncology, were pretty important to me,” he added, “because they came early and brought significant recognition.”
• Thinks that an important investment in cancer research will involve continuing to determine which of the abnormalities being identified by researchers drive the growth of cancers, and using that information to diagnose the disease much sooner in patients. “Cancer is highly curable if we can find it early,” he said.

In 1996, he met his future wife, reporter Alexandra Hardy, when she came to interview him about imatinib. They met again when she returned to interview him in 2000 and, learning of his monastic lifestyle, chided him for being “pathetic.”

It turned out that the two worked out at the same gym. They became friends, got married in 2002, and are now the parents of three children.

To make sure he has time for his family, Druker limits his travel and teaching activities and farms out many of the day-to-day tasks involved with running the center and his lab.

Commitment Grew With Experience

“I get a lot done because I can delegate to absolutely fabulous people,” he said. “I can check in and make sure everything’s going as well as I’d like it to.”It took Druker as long to adopt his hard-working attitude as it did for him to learn, later on, to counter it with a modicum of downtime.

In high school in St. Paul, Minnesota, and in college at the University of California, San Diego, everything but physics came easily to Druker—especially chemistry, biochemistry, biology, math, and computers.

“It used to annoy all my classmates,” he recalled. “I didn’t put in a lot of effort. l got it really easily and managed to break the curves in the classes.”

Druker sailed along to earn a BS in chemistry, and then was among the elite 10% of his class that was accepted into the UC San Diego School of Medicine.

As an undergraduate, Druker conducted research in molecular biology and gene cloning, and he moved on to immunology research—the stimulation of T cells and their suppression of immune response—during medical school. However, during his residency at Barnes-Jewish Hospital at the Washington University School of Medicine in St. Louis, Missouri, he turned away from research to treat patients. He continued his training with a focus on oncology patients at Dana-Farber Cancer Institute at Harvard Medical School in Boston, Massachusetts. And that’s when his passion for finding new therapies began to grow.

“Taking care of cancer patients was pretty trying,” Druker recalled. “As medical oncologists, we were treating patients with breast, lung, colorectal, and prostate cancers who had metastatic malignancies. We could help them live a little longer with chemotherapy, but that often made it worse, not better, and it cured very few. I’d always come into this with the view that chemotherapy seemed barbaric, so I had no desire to continue to treat patients that way. I decided I was going to go into the lab and not come out until I had something better—that was my commitment.”

After his fellowship, Druker stayed at Dana-Farber to join the lab of Thomas M. Roberts, PhD, whose focus was the study of oncogenes.

“I was the least-experienced person there,” recalled Druker, who was hired as an instructor in Medicine. “The last time I had worked in a lab was six years prior, or more, and lots of techniques had changed. Everybody had more training than I did.”

Rejection Led to Resolve

Yet Druker persevered.In Roberts’ lab, Druker was assigned to work with tyrosine kinases, and soon developed an antibody that could detect the modification of tyrosine residues by the addition of a phosphate. The tool showed when certain enzymes were activated, and when an inhibitor had succeeded in shutting them off. Specifically, the measurement system zeroed in on an enzyme, bcr-abl tyrosine kinase, associated with CML.

“I thought about what human diseases were caused by this family of enzymes, and CML was one of them,” Druker said. “It made sense to me to work on a disease where I had lab expertise, but also in which we someday may have been able to treat patients. It was a nice convergence of events.”

At the same time, Druker was moonlighting one night a week as medical director of Oncology at Nashoba Community Hospital in Ayer, Massachusetts, in order to keep his skills sharp when it came to treating patients.

He kept up that schedule until 1993, when he asked to be promoted to the position of assistant professor at Dana-Farber— and was refused.

“I had published quite a number of papers, most in collaboration with others at Dana-Farber and around the country,” the doctor said. “I was seeing my ideas being published by other people, which meant to me that I was ready to run a lab and work out my own ideas, but I was told that they thought other people were more worthy of investment—basically, that I didn’t have a future there. I could have stayed as an instructor forever, but I had bigger, better things to do.”

“

I still do a double-take when I see somebody who was diagnosed 15 years ago. I think, ‘How is that possible? Oh yeah, that’s right—Gleevec.’ ”

—Brian J. Druker, MD

Druker started a list of places he’d like to live and institutions that were committed to their cancer programs. As a running and cycling enthusiast, Druker thought Portland, Oregon, seemed attractive, and he knew that Grover C. Bagby, MD, had launched a cancer center at OHSU there in 1991. Upon visiting, Druker found Bagby to be “an incredibly honest, straightforward person,” and Portland to be an outdoorsman’s dream.

He left for the city and never looked back.

“When you’re told ‘You have no future here,’ you can believe it and say, ‘OK, lab research just won’t happen for me and I need to find a different career path,’ or you can become more determined,” Druker said. “I got a slap in the face and decided ‘I really want to do this, but now I need to focus, work even harder, and think more carefully about what and where it is that I’ll make an impact.’ I was much more driven than I ever had been in my life.”

With that in mind, Druker had a single goal when he headed to Portland: to find a company that had developed a compound that inhibited CML cells without harming normal ones, and to get it into patients in the clinic.

Circumstances Helped Spark Success

“I wasn’t going to stop,” he said, “until I had that.”Amazingly, all it took was a single phone call, to Nicholas B. Lydon, PhD, at the former Ciba-Geigy Corporation. Lydon previously had called upon Roberts’ lab for help in establishing a pipeline of tyrosine kinase inhibitors. Now, Lydon “thought he had compounds worth my testing,” and Druker was prepared to accomplish that with the antibody tool he’d developed at Dana-Farber.

Druker isn’t a believer in fate, but he admits that his circumstances coalesced to help make the project possible.

“It was really lucky,” he said, “but if that hadn’t worked, I didn’t plan to stop. I would have continued to call people until I found a company with the right compounds.”

Druker used his antibody tool to test the compounds, and found that one, known as STI-571, looked especially promising. The compound moved through a battery of lab tests and was transformed from an intravenous to an oral formulation after a problem with blood clots in animal subjects. In 1997, Novartis—formed through the merger of Ciba-Geigy and Sandoz— was still testing the compound, but was concerned about liver and bladder toxicity in dogs and rats.

“As an oncologist who gives extremely toxic chemotherapy drugs to patients, that didn’t look like anything that should kill the development program,” Druker recalled. “I asked if they had talked to the FDA, and they said that they weren’t ready.”

So Druker did it himself. He called someone at the FDA, described the data he’d compiled about STI-571, and asked whether the drug sounded ready to move into the clinic. Druker was told that he and Novartis had compiled more information than most companies with drugs already in clinical trials, and that the drug’s toxicity profile didn’t sound like a deal breaker.

“When I called Novartis back, they weren’t happy I had circumvented them, but it forced them to rethink whether they might get the drug into the clinic,” Druker said. “I guess if I was thinking more carefully, I would have said I needed to toe the party line or risk being taken off the project, but the right questions weren’t being asked. I just wanted to let Novartis know that the FDA agreed with me; if it had agreed with Novartis, I would have shut up.”

The phase I trials of imatinib—the first studies Druker had ever led—amounted to a hole-in-one. He presented the results at the annual meeting of the American Society of Hematology on December 3, 1999.

For Many, Druker Was “Last Hope”

“It was a standing-room-only crowd, and there was an enormous amount of excitement. You could have heard a pin drop during my presentation, and there was pretty thunderous applause at the end,” Druker recalled. “That was unusual, because the typical reaction to a phase I trial is, ‘Well, that’s interesting, but it’s still pretty early—we’ll need more studies to confirm it.’ In this case, there was none of that, just this incredible validation and genuine enthusiasm.”When he looks back at the string of events that took him into the lab to develop imatinib, Druker said it all started with his parents, who had high aspirations.

“I’m sure some of my abilities were passed along by genetics,” said Druker, whose father was a chemist, “but there was also strong pressure in my family to do something academic, the hope that at least one of the children would be a physician. My dad had always wanted to be one, and my mother’s father had, too. I was the youngest of four, and the last hope.”

Druker, shown here working with a colleague, supervises a 16-person lab.

After the phase I trials of imatinib, Druker became the last hope, as well, for patients who otherwise would have been offered bone marrow transplant or interferon as their only treatment options, and still faced life expectancies of well under a decade.

Jim Logan, a patient with CML, is grateful for every day he’s had since he was diagnosed in 1999 and flew to OHSU to ask Druker for a chance to participate in an early clinical trial of imatinib (“A Survivor’s Story,” on page 5). The Wisconsin resident was enrolled in a study that tested the drug in combination with chemotherapy, and remained on imatinib for six years. He has switched to other TKIs—including Druker’s latest, the drug ponatinib—as his cancer developed resistance.

Now 62, the husband, father, and grandfather continues to fly all over the country, working 60-hour weeks for the video production company he owns and “loving every minute of life.” He said he has Druker to thank.

“The man is incredible,” Logan said. “He’s just incredibly smart, but also incredibly personable. If there’s altruism in medicine, Brian Druker exemplifies it. Brian and his team have changed not just the face of leukemia, but of cancer research. I like to say that he has put ‘future’ back in the vocabulary of patients like me.”

Eleven years after imatinib’s approval, Druker remains as amazed as his patients at what the drug can accomplish.

“Patients in the clinic who were diagnosed 10 or 15 years ago are still doing great—living, thriving, and doing all the things they enjoy,” the doctor said. “As a medical student, I learned that the average survival for these patients was three to five years, and I still do a double-take when I see somebody who was diagnosed 15 years ago. I think, ‘How is that possible? Oh yeah, that’s right—Gleevec.’

a Survivor’s story

Videographer Pushed to Join Early Trial for Imatinib, and Is Still Going Strong

Jim Logan, a participant in one of the first imatinib trials, has taken several novel therapies during the 13 years he has lived with chronic myeloid leukemia. He took imatinib successfully for six years.

Brian J. Druker, MD, and his patient Jim Logan have something in common: They won’t take “no” for an answer.

Druker proved it when he refused to let adversity stand in the way of his development of imatinib (Gleevec), the tyrosine kinase inhibitor (TKI) that helped change chronic myeloid leukemia (CML) from an aggressive tumor type with a poor prognosis to a condition that can be managed over the course of as many as 30 years.

Logan made it just as clear when he refused to accept the news that he wasn’t eligible for early-phase trials of the drug.

When the two men met 13 years ago, they both managed to get their way. Logan entered one of the first imatinib trials and is still thriving. His success makes him a perfect example of what Druker set out to do when he buried himself in laboratory research in the early 1990s, pledging not to emerge until he had a better way to treat patients with the deadly disease.

It was during a brief phone call in 1999 that Druker told a newly diagnosed Logan he could not participate in phase I trials of imatinib because his disease was not advanced enough.

“I’m not sure what possessed me,” Logan recalled in a recent interview, “but I answered with the smartest words I’ve ever said: ‘Will you tell me that to my face?’”

Druker’s reply? “I’ll give you 15 minutes,” Logan related.

Logan, then 49, and his wife Beth flew from their home in Wisconsin to see Druker at the Oregon Health & Science University (OHSU), in Portland. Their son, Ryan, a US Air Force pilot, met them there. Their conversation with the doctor stretched past the 15-minute mark, beyond an hour, and through a second and then a third hour.

The upshot was that Logan was accepted into a phase I trial of imatinib, becoming the first patient to enroll. The trial, one of several early-phase looks at the drug, tested imatinib in combination with cytarabine, and, later, interferon. While the drugs did not prove valuable in combination, Logan remains forever grateful that he was given the chance to participate.

Diagnosis Launched Search

“That started the ball rolling, and imatinib worked successfully for me for six years,” said Logan, who later went on to take other TKIs. Logan found out he had CML after his family doctor conducted a routine blood test. On the job for the video production company he owns with his wife, Logan was getting ready to fly from Chicago to Europe when he got an alarming call from the practitioner. “I don’t want to do this over the phone,” the doctor said before breaking the news.

Logan asked if he would be dead within the next couple of weeks. When the doctor said he would not, the videographer boarded the plane.

But Logan wasn’t free from worry about his condition. His first visit to the Internet turned up a website full of memorials to people who had died from CML. Later, his doctor told him he would live 42 months unless he received a bone marrow transplant from someone considered an appropriate match.

Logan and his wife chose a transplant facility and were 21 days from the procedure, the patient recalled, when they read a brief newspaper article explaining that Druker had treated six or seven CML patients “with 100% success.” Friends began checking in to make sure the couple had seen the write-up.

Logan tried contacting OHSU, but could not get through to Druker. So the patient contacted his attorney, whose former college roommate, also a lawyer, represented some staff members at OHSU. Through that network, someone got in touch with Druker on Logan’s behalf.

When Logan finally heard from the doctor, he was elbows-deep in a video job at the Grand Ole Opry, and had been inundated, to the point of annoyance, by local friends calling to say hello.

Bond Forms With Druker

“The phone had been ringing incessantly, so when I picked it up, I was very short with the caller,” Logan said. “Then a voice said, ‘This is Brian Druker.’ I almost dropped the phone.” It was the start of a relationship that has gone beyond the clinic.

“I’ve gotten to know him, his wife Alex, and their kids, and the man is just incredible,” Logan said of Druker. “I would count Brian among my better friends.”

Since Logan’s first years on imatinib, his CML has progressed not just on that drug, but also on other targeted therapies that have sprung up in its wake to treat resistant forms of the disease.

“When you have a disease like this, it’s not always forward progression,” Logan said. “Sometimes you slide back, and that hurts. But when I failed on these drugs, it was miraculous that each time a door has opened.”

In fact, Logan participated in phase I clinical trials of every TKI currently approved for the treatment of CML, developed by a variety of researchers and pharmaceutical companies. Now, he’s come full circle by participating in a phase II trial of Druker’s latest offering, ponatinib. The drug, recently approved by the FDA, is designed to overcome all forms of resistance that can arise in CML, including the bedeviling T315I mutation.

“The amazing thing is that, within a couple of months of starting it, I went to totally undetectable leukemia and have maintained that,” Logan said. “It’s incredible.”

Logan admits that his experience with the drugs hasn’t been perfect.

“Drugs like dasatinib affected my joints,” he recalled. “It was like having very severe rheumatoid arthritis. I couldn’t put on my belt without tears running down my face, and there are other side effects with all these drugs. But what’s the alternative?

“People say, ‘Oh my God, I got a hangnail because I’m taking this drug.’ And I say, ‘Get a life.’”

“To me, it’s still remarkable to think about where things were a decade ago and where they are now.”