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

| April 10, 2014
Dr. Brian J. Druker

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.

Career Highlights “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.

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