Lasker~DeBakey
Clinical Medical Research Award

Award Presentation by Michael Bishop

At the turn of the twentieth century, the German medical scientist Paul Ehrlich took aim at the leading killer of his time: infections. Ehrlich was aware that some diagnostic stains for bacteria failed to react with human cells. This inspired him to imagine therapeutics that would behave in the same way — "magic bullets" as he called them, aimed exclusively at infectious agents and harmless to normal human tissues. Ehrlich's pursuit of his vision led to the first effective treatment for syphilis, but he never found a true magic bullet. He died a disillusioned man, regarding his life in science as a failure, unconsoled by the Nobel Prize that he received in 1908. The marvel of penicillin and numerous other antibiotics that embodied Ehrlich's vision would come later.

Although rarely mentioned, Ehrlich also imagined magic bullets for cancer. But cancer is a far more subtle adversary than infections. Cancer cells are born of normal cells, a kinship that until now has caused many of our therapies to wreak havoc with the health and welfare of cancer patients. It is fair to say that "chemo" has ranked among the most dreaded of all medical procedures. And as further insult, it rarely cures. Almost a century after Paul Ehrlich, magic bullets aimed at cancer were still eluding us. The prospects improved, however, with the discovery that cancer arises from the malfunction of genes. Each malfunction sets the cancer cell apart from the normal cell, each may be a keystone for the creation of a therapeutic magic bullet. The 2009 Lasker Award for Clinical Research honors three scientists who played a central role in bringing a full-blooded magic bullet for cancer to life: Brian Druker, Nicholas Lydon and Charles Sawyers.

The story begins in 1959, when David Hungerford and Peter Nowell discovered an abnormal chromosome in the cells of chronic myeloid leukemia (CML), dubbed the "Philadelphia Chromosome" for the home of its discovery. Some years later, Janet Rowley worked out the physical mishap that engenders the Philadelphia Chromosome. All this seemed a mere curiosity to many observers at the time. In reality, however, the foundation had been laid for the therapeutic breakthrough that we celebrate today. Nowell and Rowley eventually received the Lasker Award for their work — sadly, Hungerford was by then deceased. We now know that the Philadelphia Chromosome carries two mangled genes, joined together to encode a mongrel protein. The mongrel has no leash, and its unrestrained attack drives blood cells to leukemic growth. Since the mongrel is not found in normal cells, it is a potential target for a therapeutic magic bullet.

The first steps towards creating a magic bullet for CML were taken at the pharmaceutical company Ciba-Geigy. There a team led by Nick Lydon conducted a search for drugs that might tame the mongrel molecule of CML by inhibiting its function — an activity known as protein kinase. It was a formidable undertaking, because there are a vast number of different protein kinases in normal cells. The reigning view held that it would be exceedingly difficult, if not impossible, to create drugs that could distinguish among the numerous protein kinases, let alone selectively inactivate a single kinase such as that responsible for CML. Lydon and his team bucked this preconception and forged ahead.

The search first produced a drug that inhibited numerous protein kinases — far short of a magic bullet. But further chemical fiddling led to an inhibitor whose effects were limited to the protein kinase of CML and a few close relatives. The drug eventually became known by the trade name Gleevec, and it would prove itself worthy of the sobriquet "miracle."

At the time, victims of CML were destined for almost certain death. Even patients who responded to the onerous therapies then available knew that they had bought only time, not a cure. There was a desperate need for more effective therapy. But kinase inhibitors remained an unknown quantity as therapeutics, and since CML is not a common disease, the potential market for Gleevec seemed small. So the management at Ciba-Geigy had little enthusiasm for further development of the drug.

Enter Brian Druker, a young medical oncologist, newly appointed to the faculty of the Oregon Health and Sciences University. Druker was an accomplished student of protein kinases and had set his sights on CML. He had previously urged Nick Lydon to focus on the mongrel kinase of CML as a therapeutic target. Now the two joined forces to demonstrate that Gleevec could inhibit the growth of CML cells in petri dishes and mice, but was harmless to normal cells. These results cried out for a clinical trial with human patients. Still leery of market size, however, and concerned about the toxicity of Gleevec in dogs, Ciba-Geigy demurred.

Druker would not take "no" for an answer. He recruited an ally in Charles Sawyers, a similarly youthful oncologist at UCLA, who was himself an authority on the mongrel kinase of CML and had advised Druker during the early laboratory testing of Gleevec. The two joined in advocacy for clinical trials, taking their case directly to corporate headquarters in Basel, Switzerland. They had to wait for an answer until completion of the merger between Ciba-Geigy and Sandoz that created Novartis, but in due course, they prevailed. The results were stunning. Administered as a pill rather than an intravenous infusion, Gleevec elicited prompt and often lasting remissions of CML, and had only minor side effects. "Chemo" this was not.

Patients and physicians alike were electrified. So was the Food and Drug Administration (FDA) — a rare state of mind for that agency, which approved Gleevec in the record time of eleven weeks. The Secretary of Health and Human Services, Tommy Thompson, announced the approval himself at a press conference on May 10, 2001, in Washington, D.C. — the significance of Gleevec had not escaped his political instincts. Gleevec promptly became the poster child for what we now call "targeted therapy" of cancer, aimed at the molecular malefactors in cancer cells. A new day had dawned for oncology.

But perfection is rare in our ongoing contest with disease. Over time, microbes developed resistance to the antibiotics spawned by Paul Ehrlich's vision of magic bullets. Regrettably, cancer is capable of its own lethal recalcitrance — until now, there has been hardly a therapy that cancer cannot eventually elude. True to form, CML can become resistant to Gleevec, leading to recurrence of the disease and treatment failures. In the same year that Gleevec was approved by the FDA, however, Charles Sawyers provided the first explanation for that resistance, and has since led the way in developing drugs that can turn the tables on it. At last report, patients treated with Gleevec in the early stage of CML had a 95% chance of surviving for at least five years, and there is no reason to believe that a limit has been reached. Meanwhile, Gleevec is proving effective in the treatment of other malignancies incited by close relatives of the CML kinase.

The story of Gleevec is rich with intellectual and professional daring:

	Few scientists gave much credence to a role for chromosomal damage in cancer when Hungerford and Nowell initiated their path-breaking experiments, which constituted Hungerford's PhD thesis — few students have done better.
	Janet Rowley returned to research after raising her family and uncovered the genesis of the Philadelphia Chromosome.
	Nick Lydon and the research team at Ciba-Geigy initiated work on inhibitors of protein kinases when there seemed little prospect for such agents, and followed through to the creation of Gleevec.
	At a crucial and vulnerable point in his career, Brian Druker gambled on his vision of a magic bullet for CML and won. Charles Sawyers shared in the gamble and victory, then extended the work in ways that have further improved the prospects for victims of CML.
	The FDA knew a good thing when they saw it and moved with uncommon alacrity.
	And lest we forget: the corporate leadership of Novartis allowed themselves to be swayed by the arguments of two young and, at the time, unheralded scientists. In the offing, what was deemed to be a small market is now returning billions of dollars.

It has become fashionable of late for the press to voice cynicism about cancer research. Medical scientists stand accused of self-serving conservatism that has impeded the search for cures. The story of Gleevec provides an antidote to this dyspepsia: a stirring example of visionary research, from start to finish; and a proof of principle that promises to have a profound and lasting impact in the war on cancer.