A slow saga of success

If you’ve ever wondered why the journey from lab discovery to the clinic takes so long, follow the decades-long story of Gleevec

“Find something that interests you, and go for it.”

That’s what David Baltimore told postdoctoral researcher Naomi Rosenberg when she entered his MIT lab back in 1973. And one topic that interested Rosenberg was leukemia.

In graduate school Rosenberg had used cell culture techniques to study different diseases, but those techniques didn’t yet exist for this deadly cancer of the blood.

After perusing the scientific literature, she came across the Abelson virus, a pathogen that caused rapid tumor growth when injected in mice. “The speed with which it caused leukemia intrigued me,” recalls Rosenberg, now a professor at Tufts University Medical School.

Rosenberg began trying various methods for infecting healthy blood cells in culture. Then, in 1975, she published her success, using the Abelson virus to induce leukemia in mouse blood cells. “For the first time we had a way to study in a controlled environment how this virus interacts with its target,” she says.

What Rosenberg didn’t know at the time was that this postdoctoral success was one link in a profound—and unsuspected—chain of events that three decades later would culminate in a spectacular cancer drug: Gleevec.

Gleevec treats chronic myelogenous leukemia (CML), which strikes about one-fifth of all leukemia patients—roughly 1.5 cases per 100,000 people. Before Gleevec, the fatality rate of this disease was 100 percent.

Brought to market in 2002, Gleevec represents a revolution in cancer treatment. Rather than carpet-bombing the body with toxins that wipe out the cancer but incite a range of devastating side effects, and very often fail anyway, Gleevec targets a specific molecular abnormality of CML. Although the drug doesn’t eliminate the cancer, for the majority of patients it knocks it into a kind of permanent remission. As long as patients take Gleevec daily, CML becomes a chronic, and manageable, disease.

Gleevec points to the future of cancer treatment, but it also typifies the serendipitous nature of basic research—and the agonizingly long road that even the most dramatic success stories must follow.

“The journey from the lab bench to the clinic is a slow process,” says Whitehead Member Robert Weinberg. “Most people fail to appreciate the time it takes for a discovery to result in a drug. It would be wonderful if these things turned around quickly. But this process always has—and probably always will—take time.”

Fusing research

One can argue that the first major Gleevec-related discovery occurred in 1914 when Theodor Boveri, a German cytologist, proposed that cancer results from defects in a cell’s chromosomes. However, most people mark 1960 as the year the story began. That’s when Peter Nowell of the University of Pennsylvania and David Hungerford of Fox Chase Cancer Center noticed that cell samples from CML patients often contained an abnormally small chromosome, soon dubbed the Philadelphia chromosome.

In 1973, Janet Rowley of the University of Chicago found that this chromosome was a kind of hybrid, the result of chromosomes 9 and 21 swapping genetic material.

Between these two findings, another piece of the Gleevec puzzle was discovered—one that then lacked any apparent connection with the Philadelphia chromosome.

Herbert Abelson, then an MD at Children’s Hospital in Boston, discovered in 1969 a virus that caused leukemia in mice. (Named after its discoverer, this was the virus that Rosenberg would use to develop her cell culture platform six years later.)

Since the Abelson virus was one of many able to produce tumors in animals, scientists reasoned that viruses also caused tumors in humans. But this view was gradually overturned in the late 1970s and early 1980s, when Weinberg and many other researchers demonstrated that generally the real culprits were genetic mutations.

Still, years of research with cancer viruses were hardly in vain. In 1976, shortly after Rosenberg’s success in culturing leukemia, a new postdoc in the Baltimore lab, Owen Witte, collaborated with Rosenberg to identify the protein expressed by the Abelson virus. Like many other cancer viruses, the Abelson virus is so tiny that it produces a single major protein. Witte and Rosenberg found that this protein was a hybrid, most likely a result of the viral gene fusing with a normal cellular gene.

“This was a mystery,” recalls Witte. “We had this peculiar protein, but we still didn’t understand what it did.”

At this time, there was no obvious relation between this fusion viral protein in mice and the fused human chromosome that Rowley had found.

The human connection

Gleevec is so effective because CML has a clear target. As horrible as the disease is, all of its symptoms completely depend on a single protein, one that the drug disrupts.

In 1984, researchers from both the United States and the Netherlands discovered the strange genetic signature that produced this key protein.

Again, while human cancers generally are not caused by viruses, understanding how the virus worked, and which genes it interacted with in animals, provided scientists with clues for where to look in human cells. A team led by Gerard Grosveld, then at Genetics Erasmus University in the Netherlands, announced that it had located the human version of the Abelson virus gene. While normal human cells contain a healthy version of the Abelson gene, in CML patients, this gene turned out to be located right on the Philadelphia chromosome.

Now that scientists had the gene’s address, Witte immediately started to look for the protein that the human Abelson gene expressed. He discovered that cells from CML patients expressed an over-sized variant of the normal Abelson protein. “It was very strange,” he says.

Like the viral protein, the human CML protein was a kind of hybrid, the byproduct of two unrelated genes (the BCR and Abl genes) fusing together. Called BCR/Abl, this mutant gene on the Philadelphia chromosome created a protein that, like the gene, consisted of two components that in normal cells existed apart from each other. This was the over-sized protein that Witte had discovered in CML cells.

But observing the protein was one thing. Proving it caused cancer was another.

A silver bullet

In 1984, David Baltimore, who had become Whitehead Institute’s first Director, moved his lab across the street from MIT into the new Whitehead building. Shortly after this, MIT graduate student George Daley joined Baltimore’s group. Daley (who would eventually become a Whitehead Fellow) arrived at the lab already interested in CML in general, and in the newly discovered BCR/Abl gene in particular.

“What wasn’t clear,” says Daley, now a professor at Harvard Medical School, “was whether or not BCR/Abl was the gene that initiated the disease. Weinberg’s research, for example, was suggesting that most cancers needed mutations in a number of key genes to develop, not just one.”

Experiments with cell cultures from both the Baltimore lab and Witte’s UCLA lab suggested that the gene could transform normal human cells into cancer cells that resembled CML.

“But an animal model was still missing,” says Daley. “In order to provide the conclusive evidence that BCR/Abl was indeed the culprit, we needed to demonstrate that it, and it alone, could initiate CML in an animal.”

Many research labs were trying to do this, mostly through incorporating BCR/Abl into the animals’ germ lines. But the BCR/Abl gene was toxic to germ cells, and most of these mice died in utero.

Daley tried a different route.

Using the methods that then-Whitehead Member Richard Mulligan had developed for transferring genes into blood stem cells, Daley transferred the BCR/Abl gene into the bone marrow of mice.

He then took that bone marrow and transplanted it into a second group of mice whose own marrow had been destroyed by radiation.

And the second group of mice developed CML.

“If you think about it,” jokes Daley, “this was really gene anti-therapy.” This experiment proved that the BCR/Abl gene was sufficient to cause CML. “We now knew that for this disease, BCR/Abl was the fundamental drug target,” he says.

Killing with kinase

Back in 1980, when Owen Witte first discovered the Abelson virus fusion protein, he also found that it belonged to a family of proteins called kinases. A kinase sends messages through the cell by adding a phosphate to other proteins, which in turn affects those proteins’ activity.

What distinguished the over-sized BCR/Abl protein that Witte had identified from ordinary kinases—and from the normal Abl protein—was that because of its mutant structure, this fusion protein evaded cellular regulation. The BCR/Abl protein was a kinase gone wild.

By the mid-80s a number of researchers were investigating whether kinases could be potential drug targets. One of these was Brian Druker, an oncologist working with Thomas Roberts at Dana-Farber Cancer Institute. Druker had chosen Roberts’s lab over the clinic because he wanted to understand cancer on the molecular level. “Even though we were getting better at using chemotherapy to treat cancers like childhood leukemia, the drugs had terrible side effects,” he says. “What’s more, we didn’t even understand what they did.”

During his nine years at Dana-Farber, Druker began to focus more on CML, collaborating on and off with two Swiss pharma companies, Ciba-Geigy and Sandoz. Although few companies were investing heavily in drugs that blocked kinases, Druker was convinced that CML could respond to such a novel approach. “It was a well-defined disorder that we knew resulted from an activated kinase,” he says. “Block the kinase, and you’d topple the disease. Plain and simple.”

In 1993 Druker left Dana-Farber and took a position at Oregon Health & Science University. “I had one goal at the time: to find a company that had an inhibitor for BCR/Abl and to bring it into the clinic.”

Druker contacted Nick Lydon, a scientist at Ciba-Geigy. Lydon had developed a number of small kinase-blocking compounds that Druker wanted to test. Since kinases pass their phosphate messages by physically interacting with other proteins, almost like two Lego pieces snapping together, the hope was to find a tiny molecule that could wedge itself inside the exact spot where the two proteins fit, thus obstructing the message. The caveat was that such a molecule must be so specific that it could only disrupt BCR/Abl. And while kinases are not as uniform as a box of Legos, they are similar enough to make this a daunting challenge.

While Druker was screening Lydon’s compounds in human bone marrow cells, one named STI571 stood out. By targeting a section of the BCR/Able protein called the “catalytic cleft,” this compound immobilized its ability to transfer phosphates to other proteins. Healthy cells were unaffected.

“At that point I knew we had a potential drug,” says Druker.

In 1996, Druker and Lydon published these findings, the same year that Ciba-Geigy and Sandoz merged and formed the pharmaceutical giant Novartis. While Druker became the academic advocate for STI571, Lydon and Alex Matter, director of the Novartis Oncology Research unit, continued to push STI571 into clinical trials, despite lingering skepticism that simply blocking a kinase could hamper such a deadly disease.

On trial

The first human trials of the drug occurred in 1998. All 31 patients experienced complete remission.

Over the next four years, 6,000 people entered into clinical trials with STI571, renamed Gleevec (Glivec in Europe and Australia). After the treatment, over 90 percent of people diagnosed with a fairly early stage of the disease were free of symptoms. About 60 percent of patients with advanced CML experienced brief remission, with relapse often occurring after a few months.

“But understand,” says Druker, “for years I’d been treating patients with the disease, telling every one of them that they’d be lucky if they lived five years. And then this! This is one of the best examples I’ve ever seen of science triumphing over disease.”

“It’s unlikely that we’ll find a drug for breast or prostate cancers that works exactly like Gleevec,” cautions Daley. “These more common cancers typically aren’t caused by a single mutated protein. There are usually a few BCR/Abl-like proteins at work. But what we can do is try to develop cocktail drugs, therapies that have two or three compounds that knock out a handful of pathways at once.”

Photo: Kim Furnald

While Gleevec has also proven effective for certain rare forms of gastrointestinal cancer and the blood condition hypereosinophilic syndrome, it isn’t the only such show in town. Iressa and Tarveca, lung cancer drugs, and Herceptin, a breast cancer drug based partly on Weinberg’s research, also successfully target specific molecular signatures. Many similar drugs are in clinical trials.

Many people taking Gleevec today were not even alive when the Philadelphia chromosome was first discovered, nearly 50 years ago. During this period, our understanding of the very nature of cancer dramatically changed, and thanks to the persistence of researchers such as Druker, the genetic revolution that began in the 1970s has finally arrived at the clinic.

Still, the need for fundamental science has never been greater.

“Every once in a while I’ll hear someone suggest that we’ve done enough basic research, and now all our energy should be focused on applying it,” says Weinberg. “Nothing can be farther from the truth. There are still many signaling pathways operating within cancer cells that we just don’t know about yet. Only by meticulously researching how all these other cancers work will we be able to build an arsenal of drugs that disable this disease at the root.”