Editorial Comment:

At the 1999 meeting of the American Association of Hematologists, Dr. Brian Druker presented phase I clinical trial results on Gleevec (STI571), a new drug for the treatment of Chronic Myelogenous Leukemia (CML). The early success of this new cancer drug is unprecedented and represents a new approach in the treatment of this dreaded disease. For the first time, the molecular defect which causes a cancer has been identified and a specific drug has been developed which targets the defect and does not harm normal tissue. The implications of this approach are far reaching and is causing great excitement in the medical community as this method of attacking cancer can be applied to other types of cancer as well. This wonderful new drug did not happen over night. It is the culmination of over 10 years of selfless work by Doctor Druker and many others who have dedicated their lives to finding a cure for this disease. The World owes a great debit to these researchers who spend their lives in a quest to relieve the suffering of others. Mere words can not express the heart felt thanks that I feel for Dr. Druker and the many other dedicated men and women who have made this drug a reality.

Jerry Mayfield (Webmaster)

Below, is a brief history of Gleevec (STI571), written (at my request) by the primary research scientist, Doctor Brian Druker. Following Doctor Druker's history of Gleevec (STI571) is an article, published by the Journal of the National Cancer Institute, which adds additional information.

A History of STI 571 by Dr. Brian Druker (Left)

The Unsung Heroes.

As Judy Orem has said, drugs don't just pop off the shelves. As is the case with any drug, there is a long process before a drug reaches the stage where STI 571 has arrived. In the case of STI 571, the research effort at began at Ciba-Geigy (now Novartis) in the early 1990s. Finding a compound that works in research models is the first stage in identifying a candidate drug. The next stage, which is referred to as pre-clinical development, involves a team of individuals who perform the work required prior to human clinical testing. This time consuming phase involved a dedicated team of development scientists who studied the synthesis, toxicology, metabolism, formulation and production of the final drug. In the case of STI 571, there are several scientists who deserve particular mention. These include: Juerg Zimmermann, the chemist who synthesized STI 571, Elizabeth Buchdunger, a scientist at Novartis who did much of the original cellular profiling of STI 571 and related compounds and Helmut Mett, who was responsible for enzymology. Peter Graff, Ulrika Pfaar and Hans Michael Buerger also deserve special mention for their contribution to the success of the pre-clinical development phase of STI 571. In addition to these scientists, this project could not have progressed without the continual support of Alex Matter, who is the director of the Oncology Research unit at Novartis that discovered STI 571. Lastly, and most importantly, is Nicholas Lydon. Nick was the person in charge of the kinase inhibitor program from which STI 571 was created and Nick was the person who sent me a number of Abl kinase inhibitors, including STI 571, to test in the lab.

When I demonstrated that STI 571 had remarkable activity and specificity for CML, Nick immediately recognized the promise of this compound and is responsible for seeing STI 571 through the research and pre-clinical developmental phases. Nick and I spent countless hours discussing all of the issues required to get STI 571 to its current status, but when all was said and done, Nick actually got things done. Currently, Nick has set up his own company, Kinetix Pharmaceuticals Inc., based out of Medford, MA, to develop other kinase inhibitors, like STI 571. We owe all of these unsung heroes a debt of gratitude.

STI 571 - A Pill, No Accident

The media has dubbed STI 571, the leukemia pill. Although there are many things about STI 571 to celebrate, the media has certainly captured one of the most appealing aspects of STI 571, that is, its ease of administration. No infusions, no injections, just a pill to get rid of leukemia.

It sounds simple, but it is no accident that STI 571 is a pill. In fact, the first form of STI 571 developed was intended for intravenous infusion. In one of our many discussions about the development of STI 571, Nick Lydon and I talked about how STI 571 would be given. That is, would it be given every other week, one week of every month, or daily and for how long. It was my view that STI 571 would probably have to be given daily for long periods of time. Nick immediately recognized that for patient convenience, STI 571 should be in pill form and I agreed. Nick then put his Novartis STI 571 team up to the challenge of modifying STI 571 so that it could be formulated into a pill. The rest, as they say, is history.

My role in the development of STI 571

From the time I was a medical student I dreamed of a day when cancer therapy would be more rationally designed so that the severe side effects of chemotherapy could be avoided. I remember hoping that someday I might make a contribution that would assist in making this dream a reality. For the next seven years, I completed medical school, then an Internal Medicine Residency and an Oncology Fellowship. At that point I was ready to return to the lab to begin investigations into abnormalities that drive the growth of cancer cells. As it turns out, I began studying a family of enzymes called tyrosine kinases in the laboratory of Dr. Tom Roberts at Dana-Farber Cancer Institute. For the next five years, I devoted myself to these studies in an animal model of cancer. In the meantime, it was becoming clear that the product of the Philadelphia chromosome (Bcr-Abl) was an activated tyrosine kinase that caused CML. Through my expertise in tyrosine kinases, I was introduced to Dr. Nick Lydon at Novartis who was interested in developing inhibitors of tyrosine kinases. In one conversation that we had (in 1988, I believe), I suggested that CML would be the ideal target for his projects and predicted that CML would be the first disease where this approach would be validated. They had other targets in mind, but at least added this tyrosine kinase to their screens. In 1990, I was looking to carve out my independence from Dr. Roberts and decided that working on a tyrosine kinase that caused a human disease would be the ideal combination of my interests and expertise. Thus, CML and the Bcr-Abl tyrosine kinase seemed an ideal combination of my clinical expertise as an oncologist and my laboratory expertise in tyrosine kinase. In addition, it also fit with a long-standing interest of mine in leukemia. For all of these reasons, I forged a collaboration with Dr. Jim Griffin at Dana-Farber Cancer Institute, an expert in leukemia, and we began working on CML.

In the early days of my work on CML, we were trying to determine how Bcr-Abl causes CML. Even at that stage in my career, I tried as much as possible to relate my findings to what was going on in CML patients. Thus, in my earliest publications on CML we identified the hallmarks of the disease using patient samples. By 1993, I decided I needed to work in a place where my career could get a bit of a boost. At Dana-Farber, a part of Harvard Medical School, there are many promising young investigators and it can be difficult to distinguish oneself. Fortunately, Dr. Grover Babgy, the Director of the Oregon Cancer Center at OHSU, thought I had great promise. He recruited me and gave me money and space to expand my research program. When I moved to OHSU in 1993, I had one goal in mind -- to identify a company that had the best inhibitor of the Bcr-Abl tyrosine kinase and bring this into clinical trials. I didn't have to look very far. The first call was to Nick Lydon and as it turns out, he had several inhibitors he thought might be promising. He was quite eager to have someone test them. STI 571 was one of the compounds I received and it was clearly the best at killing CML cells while sparing normal cells. For the next four years, Nick and I worked to keep STI571 on the development track at Novartis and fortunately were successful in accomplishing this task. Interestingly, when I started working with STI571, I can think of only one other group that was taking the same approach as we were. This always seemed to me to be the most obvious and straightforward approach to the treatment of CML. However, in reviews of CML in the early and even mid 1990s, the use of tyrosine kinase inhibitors was listed as one of many possible approaches and not necessarily as the most promising. Even after we published our first paper on STI571 in 1996, I remember the mood seemed to be that this was an interesting approach, but there was much skepticism about whether or not it would work in CML patients. But it would have taken far more to have discouraged me from this approach. Things are obviously a bit different today.

What is most gratifying to me is to have dreamed about doing something like this since I was a medical student, work on the project for ten years, on STI571 for six years, and actually get to see it work in patients. It is hard to imagine a greater reward.