Hitting the Target: How Druker's Persistence Helped Launch a New Mode of Attack

Brian J. Druker, MD

Take a prognosis of three years, multiply it by 10, and what do you get? A staggering improvement in the survival of patients with chronic myeloid leukemia (CML), and a crucial steppingstone on the road to the targeted treatment of cancer.

Brian J. Druker, MD, director of the Knight Cancer Institute at Oregon Health & Science University (OHSU) in Portland, was the driving force behind those accomplishments when, in May 2001, his research led to the FDA’s approval of imatinib (Gleevec), an oral tyrosine kinase inhibitor (TKI) initially indicated for patients with CML that proved to be one of the earliest and most successful targeted therapies in the oncology armamentarium.

Today, patients with CML who take imatinib are projected to survive an average of 30 years, Druker said, a far cry from the 3- to 5-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 (Ph+ ALL) 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, as well as targeted therapies for other cancers including the TKIs vemurafenib, erlotinib, gefitinib, and crizotinib.

Most recently, Druker helped to develop ponatinib (Iclusig), initially granted accelerated approval by the FDA in December 2012, and now indicated for the treatment of patients with CML or Ph+ ALL who harbor the bcr-abl T315I mutation or for whom no other TKI therapy is indicated.

Developing Imatinib

Druker started testing imatinib in 1993, after joining OHSU as an associate professor, a member of the Department of Cell and Developmental Biology, and co-director of the Center for Hematologic Malignancies.

Previously, in a lab at Dana-Farber Cancer Institute in Boston, Massachusetts, he had worked with tyrosine kinases, developing 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.”

He hoped to take the next step—applying the measurement tool in the development of a therapy for CML—when he began his work at OHSU. With that in mind, Druker headed to Portland determined to find a promising CML treatment that he could test for activity, and then bring to patients in the clinic.

To accomplish this, he needed to find a company that had developed such a compound, one that inhibited CML cells without harming normal ones. Amazingly, Druker found what he needed with a single phone call to Nicholas B. Lydon, PhD, at the former Ciba-Geigy Corporation.

Lydon previously had called upon Druker and his colleagues at Dana- Farber for help in establishing a pipeline of TKIs. Now, Lydon “thought he had compounds worth my testing,” Druker recalled. “It was really lucky, 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.”

Pushing Through Barriers

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, I didn’t think 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 had 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 did not 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. The company gave the green light to the first trials Druker had ever led, and the phase I studies of imatinib amounted to a hole-in-one.

In one trial, Druker and colleagues found that imatinib restored normal blood counts in 53 out of 54 patients with interferon-resistant CML, 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 medication, and most reported few side effects.

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.

DR DRUKER'S SELECTED PUBLICATIONS:

• Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367(22):2075-2088.
• O’Hare T, Deininger MW, Eide CA, Clackson T, Druker BJ. Targeting the BCR—ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res. 2011;17(2):212—221.
• O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401-412.
• Tyner JW, Deininger MW, Loriaux MM, et al. RNAi screen for rapid therapeutic target identification in leukemia patients [published online May 11, 2009]. Proc Natl Acad Sci U S A. 2009;106(21)8695-8700.
• Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408-2417.
• Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99(10):3530-3539.
• Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472-480.
• Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037.
• Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2(5):561-566.
• Druker BJ, Mamon HJ, Roberts TM. Oncogenes, growth factors, and signal transduction. N Engl J Med. 1989;321(20):1383-1391.

Druker presented phase I results at the annual meeting of the American Society of Hematology on December 3, 1999, to a standing-room-only crowd.

“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, ‘That’s interesting, but it’s still pretty early—we’ll need more studies to confirm it.’ In this case, there was just this incredible validation and genuine enthusiasm.”

Imatinib was approved while phase II trials were still in progress and after an FDA review of less than three months, an all-time speed record.

Gathering Resolve

As an undergraduate at the University of California, San Diego, 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 at the same institution. However, during his residency at Barnes-Jewish Hospital at the Washington University in St. Louis, Missouri, Druker 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. 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.”

Colleagues Laud Druker’s Contributions:

Leading hematology researchers put the achievements of Brian J. Druker, MD, into context in recent interviews with OncologyLive. They noted the impact that Druker’s discoveries have had on patients with chronic myeloid leukemia (CML), as well as on the broader field of targeted therapy.

“He is a giant and a pioneer. He initially brought targeted therapy to patients with leukemia, but it opened the field wide so that everyone started looking at these targets. The development of targeted therapies led to less toxicity and more effective treatment. “This is great recognition for his contribution. I think he is one of the role models in terms of targeted therapies in this century.” - Anas Younes, MD Chief, Lymphoma Service, Memorial Sloan Kettering Cancer Center

“Dr Brian Druker’s research was the beginning of the transformative era of targeted agents. The development of a molecule that inhibited a kinase clearly transformed how we think about treatments for cancer in general. It changed our thinking from giving chemotherapy, which is not a targeted way to treat disease and which is fraught with complications, toxicities, and side effects. It transformed that thinking into targeting a specific protein, that when inhibited could achieve remission and disease control.”- William G. Wierda, MD, PhD,The University of Texas,MD Anderson Cancer Center

“What Brian Druker did was so intuitive, yet was actually quite brilliant. Druker was at the Dana-Farber Cancer Institute when David Baltimore, PhD, and Owen N. Witte, MD, were presenting data about how bcr-abl was necessary and sufficient to drive the pathogenesis of CML. Druker said, ‘Well, if we have an inhibitor against that abl tyrosine kinase, maybe it would change the natural history of the disease. After all, we use acyclovir and ganciclovir as inhibitors of the herpes viral tyrosine kinase.’ So he went about working to find, among a library of drugs, one that inhibited abl. This was incredible work which in retrospect seems so obvious, but really was quite brilliant. And that’s the beauty of science that’s well done. “The discovery of imatinib has completely changed how we treat CML and it’s meant everything to patients because the median survival prior to the abltyrosine era was somewhere around four years—if we used chemotherapy, or interferon-based regimens, a very small percentage of patients, maybe 5% to 20%, would have complete remissions with interferon. Imatinib changed everything. This drug shows deeper responses, but those are surrogates for the more important thing—it changes the progression of the disease so that the progression to phase and blast crisis is delayed, if not completely prevented. So now with 8 to 10 years follow-up in the imatinib era, the survival is about 95%."-Harry P. Erba, MD Professor, Medicine,Director, Hematologic Malignancy Program, University of Alabama

Still, Druker persevered. At the same time, he 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 was told that they thought other people were more worthy of investment— basically, that I didn’t have a future there,” Druker recalled. “I could have stayed as an instructor forever, but I had bigger, better things to do.”

Soon, he’d found the position at OHSU, where he dedicated himself almost exclusively to research, living a solitary life and working 16-hour days. His efforts paid off when the FDA approved imatinib.

CML Still a Focus

In the dozen years since, Druker’s life has changed—and stayed the same. Druker still spends a fair amount of time conducting research in his 16-person lab at OHSU, where he remains focused on finding new and better treatments for CML and other leukemias. Of particular interest has been overcoming the resistance to imatinib that arises in about 15% of patients with CML within five years of beginning treatment.

Until recently, while there were already three TKIs on the market for refractory CML, “There was still one mutation that none of those drugs would shut down—T315I,” Druker said. “We worked for close to six years testing drugs that Ariad Pharmaceuticals designed until we identified one that shut this down,” Druker said. “The drug, ponatinib, works incredibly well against that mutation and also across the board in CML.”

The bulk of Druker’s remaining time is filled 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. 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, 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. Druker’s contributions have made an enormous difference to patients with CML, including one man who said that the doctor’s work “put ‘future’ back in the vocabulary of patients like me.” Druker remains just as amazed at what imatinib, and now ponatinib, 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,” he said. “I think, ‘How is that possible?’ To me, it’s still remarkable to think about where things were a decade ago and where they are now.”