Cancerous Hens and Constipated Mice

When Ken was strong enough to contemplate a trip to Boston to see Demetri, he and Peggy were already more knowledgeable about gastrointestinal stromal tumors than most physicians are. And they wanted to learn much more. Ken rapidly became fascinated by the energy and expertise that Demetri and his team were pouring into sarcoma research.

For the moment, Ken did not need any treatment because he had no detectable disease. The cells that had been scattered around his abdomen when the tumor ruptured had not yet formed new cancers. But Ken knew that time would change the situation. Sooner or later, his abdomen would become full of GIST tumors, and they would kill him if they were not stopped in their tracks.

Demetri explained that the moment had come when the cause of GIST had been determined. Drugs that can kill the tumor were about to become available. Ken would soon be able to try a new drug that might combat GIST. The doctor's team was about to conduct tests on imatinib (Gleevec), which had just been tested successfully in chronic myelogenous leukemia (CML). Ken and Peggy became medical sponges, soaking up knowledge about GIST and Gleevec as fast as Demetri and the Internet could produce information.

The story about how GIST was identified, how Gleevec might ameliorate it, and the start of the present cancer treatment revolution has its roots in the nineteenth century when a strange cancer epidemic was repeatedly sweeping through U.S. poultry farms where hens were packed tightly together. Typically the affected birds would develop swollen bellies and gasp for breath. When the hens were cut open, their abdomens were full of masses of cells—cancers. Or, less commonly, the birds would grow large tumors on their wings. In most outbreaks the tumors seemed to be masses of white blood cells, but some of the time the tumors appeared to be sarcomas that grew out of the tendons and other supporting structures of the wings. Poultry farmers were desperate. When one bird developed a tumor, the whole flock would get cancer and die—an economic crisis for the producer.

The situation seemed insoluble, since no scientist had even considered that cancer could be infectious. Experts had only established that cancer is a disease that might be caused by an external toxin. "No relationship could be conceived to exist between the invisible viruses and the self-sufficient growth of cancer cells," George Klein of the Royal Karolinska Institute in Stockholm stated many decades later about the situation. (He said this to the distinguished assemblage before the presentation— made almost six decades later—of the 1966 Nobel Prize to Peyton Rous, who deciphered the case when the ravages were at full force.)

The mystery intrigued Rous, a doctor who had accepted a full-time appointment to direct cancer research at the newly created Rockefeller Institute of Medical Research in New York. (The institute would subsequently become Rockefeller University.) In 1910, Rous, who had been brought up with animals on a Texas cattle ranch, discovered that a virus apparently caused the cancer that afflicted the hens.

It is remarkable that Rous reached this conclusion, since the causes of cancer were virtually unknown at the time. The most relevant previous work was that of Theodor Boveri (1862—1915), a German biologist who had demonstrated that most cancer cells have abnormal chromosomes, the elements of heredity. Boveri's findings had suggested that cancer is due to mutations of genes.

Rous had started the work after a poultry farmer brought a cancerous chicken with a wing sarcoma to his new laboratory at Rockefeller. The researchers minced up the cancer and suspended the chopped cells in water. The mixture did not include any intact cells. Yet after Rous injected the material into the wings of normal chickens, they developed sarcomas, which meant the cells had to be associated with a tumor-causing agent.

Rous next fractionated the mixture of minced tumor cells by filtering it through progressively narrow filters. He kept filtering until the material did not show anything visible, even when viewed under a microscope. But chickens injected with the seemingly empty fluid also promptly developed tumors. Rous concluded that a virus—a particle so small it could pass through any filters to which he subjected the material—must be causing the tumors.

The report of Rous's experiment landed on the medical science community with a dull thud. No one doubted the result, but very few believed that a virus might cause cancer. And those who bought the argument figured that the virus must be restricted to birds. After all, Rous tried to do the same experiment with mouse and rat cancers, but he never saw the same result. Even fifteen years later, Alexis Carrel, a highly distinguished researcher at Rockefeller, dismissed Rous's results, ascribing them to the presence of some cancer-causing toxin such as arsenic in the extracts.

Finally, after many years and much more research, other scientists began to recognize that tumor viruses could cause some cancers in rats, mice, and even humans. At age eighty-seven, Peyton Rous was finally awarded a Nobel Prize for his discovery. (Ironically, Alan Hodgkin, Rous's son-in-law, shared a Nobel Prize three years earlier for his work in another field, nerve conduction.)

Though Rous's work was eventually vindicated, the mechanism by which the sarcoma virus (now known as the Rous sarcoma virus or RSV) actually causes cancer was unknown for many more years. An understanding of that mechanism was critical to investigators who hoped to find a way to kill off the cancer or sarcoma that might be related to it.

The effort to figure out the mechanism started in the late 1940s and early 1950s when Renatto Dulbecco and Salvador Luria, two Italian expatriates who later received Nobel Prizes, initiated basic research and training programs in molecular biology at Indiana University and later at the California Institute of Technology (Dulbecco) and the Massachusetts Institute of Technology (Luria). The scientists they trained, and in turn the students of those scientists, played key roles not only in the biology of RSV and the like but also in making major basic discoveries about proteins, genes, DNA, and the related structure RNA in the second half of the twentieth century. Because of that work, we know that our twenty thousand to twenty-five thousand genes (the exact number is still in question) are large molecules known as polymers. They are made of DNA and lie along stretches of chromosomes in the nucleus of cells. DNA produces very similar polymers known as RNA, which in turn engage the protein-making machinery in the cells. In that fashion, each gene produces an RNA copy, and the RNA produces the protein governed by the gene. A mutation in DNA thereby causes a mutation in its RNA and thus disturbance of the protein's structure—its sequence of building blocks called amino acids. The change in structure can alter the function of the protein and result in disease.

The importance of the molecular biology program at Indiana was at least twofold. Dulbecco and Luria focused on two types of tumor viruses: those made of DNA and those made of RNA. Furthermore, they and the scientists who at one time or another worked with them mentored several generations of researchers, some of whom eventually won Nobel Prizes. James Watson, who became famous for his work on determining the physical structure of DNA, for which he shared a Nobel Prize in 1962, began his training in that Indiana program.

In the mid-1960s, Howard Temin, trained by Dulbecco in California and, at the time, a faculty member at the University of Wisconsin, proposed a heretical notion. He argued that when an RNA tumor virus enters a host cell's nucleus, a viral enzyme transforms its RNA into DNA, which is then incorporated into the DNA of the host cell's chromosomes. The action forms new host genes, which in turn produce more viral RNAs and thus more viral particles that leave the cell and go on to infect other cells.

Temin's idea seemed preposterous: the central dogma of what became known as molecular biology had been that DNA makes RNA, which makes protein. Nobody of consequence thought RNA could produce DNA. But in the early 1970s, Temin and David Baltimore, who had also worked with Dulbecco in California before joining Luria's department at the Massachusetts Institute of Technology, separately and simultaneously discovered reverse transcriptase, the viral enzyme that converts RNA to DNA. The discovery exploded the dogma, explained the life cycle of RNA tumor viruses, earned Temin and Baltimore a Nobel Prize in 1975, and led Michael Bishop and Harold Varmus to solve the mechanism by which the Rous sarcoma virus causes cancer, for which they also received a Nobel Prize, in 1989.

Bishop and Varmus, two physician scientists at the University of California in San Francisco (UCSF), had had much of their scientific training at the National Institutes of Health (NIH) in Bethesda, Maryland. Varmus, the son of a Long Island physician and grandson of an immigrant hatter, and Bishop, the son of a Lutheran minister whose family lived for generations along the Susquehanna River in a small town near Gettysburg, Pennsylvania, met in California shortly after Bishop had established a laboratory at UCSF to study tumor viruses. Varmus, who had just completed his initial laboratory training at NIH, had gone on a backpacking trip to California, where he wanted to find a postdoctoral training fellowship. He met Bishop on that trip, and they decided to work together.

Using laborious methods that have been completely supplanted in the present era of molecular biology, Bishop and Varmus showed that at some time in the distant past a benign strain of the Rous virus had invaded and incorporated its three RNA genes into the DNA of the cells of a host chicken. To do so, the virus had to copy its RNA into DNA with the reverse transcriptase enzyme and insert that DNA into the chicken cell chromosomes.

Errors can happen when reverse transcriptase does its work because many steps are involved. What can go wrong will go wrong. At least once, the reverse transcriptase "forgot" its role and began to copy an RNA derived from a gene that belonged to the chicken. It then copied the chicken RNA incorrectly and inserted that incorrect copy into the host chicken cell's DNA. That left the cell with a DNA blueprint to fabricate a virus with four genes instead of three. The fourth abnormal gene produced a mutated protein that causes cells to proliferate wildly, resulting in cancer. Bishop and Varmus called the new cancer-causing gene src (pronounced sarc), because it was found in the mutant Rous sarcoma virus.

Src represented a new class of genes. Bishop and Varmus coined the term oncogene (meaning a tumor-causing gene) to describe the mutant src gene and others in that class. And they firmly established that the src onco-gene arises from a perfectly normal cellular src gene they called a proto-oncogene. The idea was that certain normal genes in cells such as the normal src gene could be changed or mutated to become lethal oncogenes and that cancers could become dependent on oncogenes for their survival.

The Rous virus now had a basic molecular explanation. The cause of the crisis in the henhouse had been determined. And a huge step had been taken in cancer genetics. If the protein product of a single gene could cause and maintain cancer, finding a drug that would inhibit that protein's function and cure the cancer should be possible.

Toward that end, investigators had to do more research. By the early 1980s, several laboratories had demonstrated that the src proto-oncogene encodes a normal enzyme that transfers signals through a chain of proteins that end within the cell nucleus. Those signals control the expression of genes regulating cell division and other critical functions within the cell. Fully functional tyrosine kinases—the Greek-based name for these enzymes—contribute to a network of hundreds of signaling proteins that work together to regulate cell division, normal cell death, and the functional destiny of cells. But if a mutation of the src proto-oncogene disrupts the amino acid sequence of the src tyrosine kinase protein, then the protein can become hyperactive. By passing too many signals through the kinase chain to the cell's nucleus, the abnormal protein, now an onco-protein, causes rapid-fire cell division and cell growth—that is, cancer.

Nineteen years after beginning his collaboration with Varmus, Bishop reported in his Nobel lecture that twenty-five oncogenes had been detected worldwide. Two of these, abl and kit, have turned out to play key roles in Ken's cancer. Kit played the more essential role in generating the GIST tumor that almost killed Ken.

The kit oncogene received its name for a simple reason: it was first discovered in kittens burdened by an RNA tumor virus that causes leukemia in cats and kittens. Investigators found that an RNA tumor virus had stolen a normal proto-oncogene from cat cells and then mutated it to become an oncogene. Other research showed that normal kit proto-oncogene is not restricted to cats; it exists in all mammalian cells, including those of humans.

Normal kit protein, the product of the kit proto-oncogene, turned out to be a tyrosine kinase, with one difference from either the src or the abl proteins. The kit protein pushes its head through the cell membrane and waves it in the fluid surrounding the cell. The rest of the protein, including its signaling tyrosine, lies in the body of the cell, waiting to pass signals when an external protein latches onto and combines tightly with the waving head.

This kind of tyrosine kinase, known as a receptor tyrosine kinase, is particularly useful in the development and proliferation of cells during the maturation of a fetus. Specific proteins in fluids around fetal cells that bind to receptor tyrosine kinases can start selected populations of fetal cells to divide and differentiate in order to become organs or parts of organs. Researchers have found that mice lacking essential receptor tyrosine kinases like kit or one of the specific binding proteins have different congenital abnormalities ranging from anemia and hair color loss to defective organs.

The understanding of kit's usual role in the body started with work back in the late nineteenth century when the Spanish neuroanatomist Ramón y Cajal explored the neural cells of the gastrointestinal tract. Cajal, who went on to receive a 1906 Nobel Prize for enormous contributions to neuroanatomy, had become fascinated by a rather homely mystery. As we sit enjoying a meal, we may feel the rumble of gas in our intestines. The noise signals that the bowel is doing its job—moving digested food and its accompanying gas from intake (mouth) to exit (the other end). Wavelike contractions that take place within the intestine in a synchronized manner called peristalsis regularly move the bowel contents along. Cajal wanted to know how the muscle of the bowel receives instructions to contract in this way.

The answer involved recognizing that a layer of bowel tissue contains a complex network of nervelike cells. The cells—now named for Cajal—are large and have multiple short extensions that protrude from their outer walls. The extensions of one such cell wrap around those of neighboring Cajal cells, in turn forming an ideal structure for passing along signals. Since the extensions also burrow into and connect with bowel muscles, a signal originating in a distant Cajal cell can lead to a particular segment of the bowel muscle contracting. (Without the nervelike Cajal cells, peristalsis would cease and we would be subjected to even more advertisements on television about constipation.)

Despite Cajal's elegant anatomical description of the cells named for him, proof that they actually control peristalsis did not emerge until 1995. In that year, Alan Bernstein—the current president of the Canadian Institutes of Health Research—reported that mice born without a functioning kit gene have plenty of trouble. Such unfortunate mice cannot produce the kit receptor tyrosine kinase. Bernstein had known for years that they have small eyes, abnormal coat color, and poor sperm and blood cell production. But in 1995 he observed that the mice are also chronically constipated. What defines a happy mouse is one that drops stool all over the place as it frisks around. But these mice are sluggish and unhappy; some can go days without a stool drop. They are very deficient in Cajal cells, and the few Cajal cells in their intestines lack the kit protein. Clearly, Cajal cells do drive peristalsis, and those cells cannot develop unless they are well endowed with kit.

Three years later, pathologists working in Sweden applied Bernstein's mouse studies to human cancer. Ken's tumor and others like it had originally been given a vague descriptive name because no one actually knew its cell of origin. The Swedish pathologists, suspecting Cajal cell origin, used a special stain for kit protein and found that the tumor cells stained heavily. They concluded that GISTs must arise from a cancerous Cajal cell.

One more step was necessary. Working half a world apart one year after Ken's diagnosis, Yukihiko Kitamura, a pathologist then at the Osaka University School of Medicine in Japan, and a team that included Marcia Lux, a Harvard medical student, and Jonathan Fletcher, a pathologist at the Brigham and Women's Hospital in Boston, published startling reports. They found that malignant Cajal cells in GISTs are loaded with excessive kit activity, and at least one of the two kit genes in the tumor is mutated. Kitamura had previously described rare families with inherited GISTs. In such families, the germ cells (eggs or sperm) also carried mutations in the kit gene.

Although the amount of kit protein in GIST cells is normal, its activity is enormous. Acquired GIST comes about when one of the millions of Cajal cells in the bowel suffers a mutation in one kit gene, so it produces an oncoprotein that stays active continuously. In perfect oncopro-tein form, it then ceaselessly passes signals to the cell's nucleus telling it to divide. Overwhelmed, the nucleus divides and replicates rapidly, as do its daughter cells and those of future generations. The signals also enhance the cells' survival. A large tumor forms.

That is just what happened to Ken. The multiplying and long-lived Cajal cells, driven by mutant kit, eventually created a grapefruit-size mass in his intestine. As the mass enlarged, further changes occurred in some of the cancer cells: Their chromosomes broke and rearranged themselves, creating mutations in genes other than kit. The multiple mutations added fuel to the fire of unrestricted growth.

When the size of Ken's tumor reached a critical point, the cells in the middle of the cancerous mass could not receive enough blood to sustain them. As they died, they released proteins that circulated in the blood, traveled to the liver, and stimulated the liver to release the protein that causes storage cells to bind up iron and take it out of circulation. The captured iron could not become part of developing red blood cells, which caused Ken to become anemic and fooled his specialist into believing he was iron deficient. No wonder the blood transfusions didn't work.

The cancerous cells kept growing on the outside of the tumor and dying within it. Some virtually obliterated a small segment of Ken's intestinal wall. Finally, his intestinal contents spilled out and catastrophe ensued. Then it was up to Demetri to find a treatment to kill the multiple GIST tumors that would surely grow in Ken's abdomen.

By the time I met Ken, Demetri had already directed his new patient's curious mind to a trove of information about the treatment he would receive and the various approaches Demetri would take to determine the extent, if any, of his recurrent disease. Demetri needed to educate Ken carefully because his treatment plan was not standard. Not many patients with GIST also have a ruptured small intestine. The process of obtaining useful informed consent would require plenty of patient education. Much of the education would center on the influence of particular genes on his cancer and the smart drugs that would be used to destroy it.

The discovery of the smart drug for Ken had begun more than forty years before he had met Demetri. In 1960, the genetics laboratory of Peter Nowell and David Hungerford at the University of Pennsylvania had adopted what was then a new method for examining the chromosomes of cancer cells that had been induced to grow in a plastic or glass dish. They looked down their microscopes at the twenty-two pairs of chromosomes of the blood cells of patients with the rare leukemia called chronic myelogenous leukemia (CML) and saw something remarkable. They were all normal except that in every leukemic cell of every patient, one of the pair of chromosome 22s (small chromosomes to begin with) was even shorter than its small partner. For Nowell and Hungerford, the appearance of the chromosomes, particularly the easily discernible, small 22 that became known as the Philadelphia chromosome, provided an important diagnostic test for CML. They published the finding immediately. Now, they thought, CML could be diagnosed unequivocally.

That observation, startling at the time, was the beginning of the development of an effective treatment for Ken. Thirteen years later, Janet Rowley, a geneticist at the University of Chicago, looked even more carefully at the blood cells of patients with CML and noticed that one of the pair of the larger chromosome 9s seemed longer than its partner. Within the next three decades, other scientists, particularly David Baltimore and Owen Witte at MIT, confirmed that the Philadelphia chromosome and the slightly longer chromosome 9 are due to breaks near the middle of chromosome 22 and at the tip of chromosome 9. The large broken-off piece of chromosome 22 is transferred to the breakpoint at the tip of the fractured chromosome 9, making it longer than normal. In exchange, a very small fragment of the broken-off chromosome 9 is transferred to the breakpoint on the fractured chromosome 22, leaving it considerably shorter than normal. This kind of exchange is called a reciprocal translocation as also described in Mario's story.

All of this would be interesting biology and nothing more if it were not for the remarkable fact that the translocation that produces the Philadelphia chromosome is responsible for leukemia. Reciprocal translocations probably occur in dividing cells frequently. After all, every time a cell divides, twenty-two pairs of chromosomes and two sex-determining chromosomes line themselves up, duplicate, and dump themselves properly in the nuclei of dividing cells. There have to be occasional errors in such a complex process. That a few errors such as translocations occur during cell division in several of the swarm of cells that are dividing in us every day is not at all surprising. Fortunately, the cells that bear such errors usually die, so we never see them. But some translocations—such as happened in Mario's MLL or that which causes the Philadelphia chromosome—favor a cell for survival. And the progeny of such survival-advantaged cells with "favorable" translocations appropriate the bone marrow.

In the case of CML, the reason for the takeover is now readily explained. Included in the tip of chromosome 9 that is transferred to chromosome 22 is the normal tyrosine kinase gene known as c-abl. It produces one of the more than five hundred enzyme proteins called kinases that normally work quietly together to regulate the growth of cells. CML is due to a single event in one bone marrow cell. In that cell, an innocent c-abl gene, yanked from its normal resting place on chromosome 9, is plastered onto the remaining bit of a broken chromosome 22 (the Philadelphia chromosome) at a DNA site called bcr (breakpoint cluster region).

While the broken-off piece of chromosome 22 that ends up pasted onto the remaining tip of chromosome 9 can be forgotten, the forced union of bcr DNA with abl DNA on the Philadelphia chromosome forms an abnormal gene that produces a new and much longer fusion protein called bcr-abl. That fusion protein, like the mutated kit protein that attacked Ken, has much more tyrosine kinase activity. It is an onco-protein like src, and the bcr-abl DNA is an oncogene. The reciprocal translocation transforms a formerly innocent c-abl into a monster. The constant signaling from the bcr-abl tyrosine kinase becomes a driving force that demands cell growth. It influences the bone marrow cell in which the translocation occurs to divide and avoid the death pathway. The result is chronic myelogenous leukemia. Unlike the translocation that occurred in Mario's bone marrow and forced activation of MLL, the bcr-abl translocation does not require a second "hit" to initiate leukemia. George Daley, a young medical student in David Baltimore's laboratory at MIT, showed in 1990 that bcr-abl can cause leukemia by itself just as activated kit can itself force a Cajal cell to form a gastrointestinal stro-mal tumor.

Since the discovery of the Philadelphia chromosome, nearly all leukemias, including Mario's MLL leukemia, have been shown to be due in part to reciprocal translocations; tyrosine kinases have been demonstrated to play a role in causing GIST sarcomas, breast, colon, and thyroid cancers, as well as some leukemias. Researchers have also found that many types of cancer develop from mutations of other growth-promoting or death pathway—controlling genes. Modern cancer genetics has grown out of one simple observation made by three investigators peering down a microscope at the blood cell chromosomes in a rare leukemia.

Effective treatment for Ken emerged from an initial attack on the bcr-abl oncoprotein. The abl tyrosine kinase gene in its rightful location on chromosome 9 is, like the src tyrosine kinase that intrigued Michael Bishop and Harold Varmus, one of many signaling kinase genes in cells. A kinase protein passes growth signals along the cell-signaling network by moving high-energy phosphorus molecules from one protein to an other, just as relays pass messages along phone lines. The abl gene, when normally present on chromosome 9, is almost always quiet and cooperative, switching on and off when required, but when it is fused to bcr DNA on chromosome 22, the fusion keeps the abl kinase in the "on" position. The result is a surfeit of abl kinase activity in the cell. The excess kinase activity bursts out of the confines of the signaling controls of the cell and causes unbridled growth or cancer. To pursue the phone analogy, the line is always open.

There matters stood for a while as the information percolated through the scientific and pharmaceutical company communities. Alex Matter, then a science leader at Ciba-Geigy Pharmaceuticals in Switzerland, is a bright man who reads omnivorously. Most of the information about src and abl was available to him when he decided to launch a major research effort in the 1980s to find drugs that would inhibit tyrosine kinases in human cancers. But he needed a model screening system with which he could efficiently test the huge libraries of small molecules that Ciba-Geigy had in its secret possession. He found the major tools for his screening system at Dana-Farber Cancer Institute in the laboratories of Tom Roberts and Chuck Stiles. Their collaboration rapidly led to the first antikinase therapy for fighting cancer.

Roberts and a fledgling clinical fellow, Brian Druker, provided Matter and his team at Ciba-Geigy (which would become Novartis in 1996 after Sandoz Pharmaceuticals merged with Ciba-Geigy) with a screening test that detects drugs active against tyrosine kinase proteins. Together they produced a monoclonal antibody called 4G10 that detects tyrosine when a molecule of phosphorus is bound to it. The antibody would therefore detect an activated tyrosine kinase, and it could be used in a screen to find drugs that inhibit the process. Stiles provided a precious cell line that heavily expressed a tyrosine kinase known as PDGFR.

Activated abl, PDGFR, or kit have similar functions and modes of action—they send signals to the nucleus of cells to instruct them to divide, and they do so when a molecule of ATP (the energizer of the cell) bearing a "hot coal" of high-energy phosphorus pops into its special pouch in either protein. Resting there, ATP hands the "hot coal" to a nearby tyrosine, an amino acid in close proximity to the pouch. The transfer of the "hot coal" to tyrosine starts a stream of divide now signals to the nucleus through multiple protein kinase connections.

The 4G10 antibody and the cell line allowed Matter and his colleagues to detect any drug blocking the capacity of ATP and a tyrosine kinase like PDGFR, abl, or kit to add a phosphorus to tyrosine. Thus armed, Matter's team screened thousands of small molecules for their ability to block the binding of ATP in the pouch of the PDGFR tyrosine kinase protein. Such small molecules, they reasoned, might act as effective drugs that could block kinase-signaled cell division and thereby arrest cancer. The researchers would have to be lucky, of course. They had a haystack of small molecules in which they would have to find one or two needles—drugs that would be readily absorbed in the gastrointestinal tract, penetrate cell membranes, block the ATP-binding pouch in the target tyrosine kinases, have very low toxicity, and be reasonably specific for the target tyrosine kinase.

Incredibly, the investigators went on to find several needles: three compounds out of the many thousands that they screened seemed to work. One of them, with the code name STI-571 (signal transduction inhibitor 571), was particularly effective. It was soon to be named Glee-vec. The next question was more complicated: What should Ciba-Geigy do with the drug? Serendipity came to the rescue.

In 1989, when Druker was starting his research career in the Roberts laboratory, he was well aware of chronic myelogenous leukemia because he had taken care of patients with the disease. He knew it was caused by a translocation that mutates the abl tyrosine kinase and makes it hyperactive. Immediately upon entering the laboratory, he learned of Matter's discovery of STI-571 and the inhibition of PDGFR. Druker asked a simple question: Could STI-571 also inhibit bcr-abl and thereby attack CML cells? He set about to convince Matter to develop STI-571 to treat CML.

Persuading Matter was relatively easy, but Druker found that purveying the notion to the skeptical drug company was a very tough sell. Matter's superiors in the business office at Ciba-Geigy (Novartis) were not impressed. They couldn't see how all the expensive research could translate into an effective drug for cancer treatment, especially for a relatively uncommon cancer. (At most, CML afflicts perhaps twenty thousand patients per year in the United States.) And the company had already decided to see whether the drug might prevent coronary artery grafts from narrowing by inhibiting PDGFR, which probably plays a role in that complication. Furthermore, at the time, no clear evidence existed to prove that overactive tyrosine kinases cause common human cancers.

The development of a new drug is hugely expensive. Millions must be spent on toxicity trials in animals and in toxicity and early efficacy trials in people. Plus, most drugs fail—and they tend to do so after much money has been spent on developing them. Ciba-Geigy (Novar-tis) would do far better by investing in making a copycat drug or creating something for big-market problems such as coronary narrowing, pimples, hair loss, or limp erections.

In order to test STI-571 in CML, the company would have to make enough of the experimental drug to go beyond the screening that it had pursued with the test provided by Roberts, Druker, and Stiles. That would cost money and use up the precious time of medicinal chemists who could be working on problems much more common than CML. But Druker, who had just moved to a new laboratory at the Oregon Health and Sciences University, persisted. Matter finally gave him a small supply of STI-571 for laboratory studies.

It worked—tremendously! In the laboratory, it killed CML cells that Druker had been given by Jim Griffin, one of his mentors at Dana-Farber. Druker began to beat the drum ceaselessly on Matter, imploring him to persuade Novartis to make enough of the drug for a phase 1 clinical trial.

Druker won. The trial proved hugely successful. CML patients went into remission with little or no toxicity, and Novartis received the best publicity any big pharmaceutical company had gained for several years.

Sidney Farber's magic bullet seemed to have arrived. Druker and the Novartis team received one prize after another. Sadly, Roberts and Stiles were barely noticed, but their work had established an approach to an effective treatment for thousands of leukemia patients and would soon translate into a new treatment for Ken and many others like him.

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