> > After decades of molecular research, a cancer drug leaves the lab - Janet Rowley's 1972 discovery paved the way for a leukemia-targeting drug.

When interferon chemotherapy failed to curb John Loecke's chronic myeloid leukemia, University of Chicago oncologist Richard A. Larson recommended a bone-marrow transplant, a risky but sometimes curative treatment for Loecke's form of blood cancer. With seven brothers and sisters, the 58-year-old retired middle-school principal had a good shot at finding a compatible donor. But no sibling matched, and Loecke's white blood-cell count rose dangerously high. He had already survived for three years since learning he had this leukemia; the average life span after diagnosis is four years.

Until recently Loecke's only option would have been to hope for a miracle and expect imminent death. Instead, a year ago Larson enrolled Loecke in a trial of Gleevec, a drug heralded as the first big breakthrough in cancer treatment since Nixon declared war on the disease in 1971. The three-year-old drug grew out of four decades of research, including a fundamental discovery by U of C physician Janet Davison Rowley, PhB'45, SB'46, MD'48, the Blum-Riese distinguished service professor of hematology and oncology. Rowley was the first biologist to give credence to the theory, now proven, that chronic myeloid leukemia, or CML, is genetic and caused when chromosomes within a white blood cell trade places. Her 1972 observation laid the foundation for studies leading to Gleevec's development.

Since its 1998 introduction, Gleevec has brought more than 90 percent of newly diagnosed CML patients into remission, with few side effects. And although Loecke was diagnosed a while ago, it is working for him too.

The drug has gotten lots of press, and CML patients are eager to try it. It's clear why, says Larson, who directs the leukemia program at the Medical Center's Cancer Research Center. "You'd prefer a magic bullet over a shotgun. It's a targeted agent that has little collateral damage, is well tolerated, and seems quite effective. Yet it serves a small market." About 4,500 Americans are diagnosed with CML each year, compared with 170,000 lung cancer and 190,000 breast cancer diagnoses.

But Gleevec's significance extends far beyond CML. It is considered the vanguard of "rationally" developed drugs, those based on understanding cancer cells at a molecular level. Unlike chemotherapy and radiation-which indiscriminately kill all rapidly dividing cells-"molecularly targeted" drugs interrupt specific processes in a particular cancer, killing only the cancer cells. In CML a faulty signaling protein in white blood cells triggers nonstop replication. Gleevec jams the protein's message receptors, and the mutant cells stop dividing.

Gleevec is important, says Larson, "not just because this is a new and better medicine for an otherwise lethal disease. It's a validation of the investment that's been made in the last 35 years in basic cancer research."

Some of that basic research was done by Rowley, who at age 76 still works just a short walk from the clinic where Loecke goes to see Larson each month. Her interest in genetics grew out of working with children with Down's syndrome, which in 1959 was linked to an extra chromosome 21. The next year, on sabbatical in Oxford with her husband, Donald A.

Rowley, SB'45, SM'50, MD'50, professor emeritus of pathology, she decided to learn more about chromosomes. Her studies led her into cancer research. A decade later, again in Oxford, she encountered a new technology for staining chromosomes and began using the banding techniques to study the genes of leukemia patients. Rowley knew that in 1960 two Philadelphia physicians had observed that patients with CML usually had one abnormally small chromosome. Perhaps it was chromosome 21, perhaps 22; technology wasn't advanced enough to tell for sure. Nor was it clear what happened to the missing fragment. But with chromosome banding, Rowley could see more-and answer these questions. One autumn afternoon in 1972 she noticed something very exciting: white blood cells of patients with CML not only had a short chromosome in pair 22, but they also had a longer-than-usual chromosome in pair 9. Parts of chromosomes 9 and 22, it seemed, had changed places. Rowley theorized that the chromosome breaks and the abnormal joining of 9 and 22 must somehow cause CML-rather than being caused by it, as most physicians believed.

"There was very little interest in this outside the community that studied chromosomes," she recalls. She herself did not know where the discovery might lead.

A quarter-century later, in 1998, Rowley received the Albert Lasker Medical Research Award for that autumn observation. In 1999 President Clinton presented her with the National Medal of Science. Her long career at Chicago has included appointments not only in the departments of medicine, molecular genetics and cell biology, and human genetics, and the Committees on Genetics and Cancer Biology, but also, this spring, as interim deputy dean for science in the Biological Sciences Division.

Although in 1972 Rowley was unable to explain why the trading of genetic material makes white blood cells go haywire, she had provided the map for other investigators. Knowing where chromosomes exchange material helped pinpoint the locations of genes most likely to be altered by translocation. The next task was to identify the genes at the breakpoints and explore how damage to them makes cell function go awry. That was accomplished in the 1980s, when investigators discovered that the 9;22 translocation juxtaposes parts of two genes to form an altered gene. This fused gene, in turn, produces a new protein named for the fractured genes that combine: BCR-ABL.

The ABL gene had been identified in 1969 by Herbert T. Abelson, now the George M. Eisenberg professor and chair of pediatrics. Then at the National Cancer Institute, Abelson isolated a gene found in a mouse leukemia virus. Named after Abelson (and abbreviated ABL), the gene was later found to have a human copy. Researchers pursuing Rowley's discovery of the 9;22 translocation recognized ABL as the gene that breaks off and migrates from chromosome 9 to 22. His research, says Abelson, "had nothing whatsoever to do with anything clinical at the time. It was a very different line of research. That's the importance of basic investigation: if you do good work, it may lead to unexpected downstream consequences, as happened here."

Once scientists had identified the BCR-ABL protein in people with CML, the next step was to discover the protein's cellular function. In the mid-1980s the protein was found to be a tyrosine kinase enzyme, which regulates cell division. Oregon Health & Science University physician Brian Druker discovered how the BCR-ABL protein initiates a cascade of reactions leading to nonstop cell replication. He collaborated with the drug company Ciba-Geigy, which was developing a "library" of small molecules that might block the tyrosine kinase signaling proteins. Gleevec, it turned out, did best at blocking the BCR-ABL protein while leaving normal cells unharmed.

Novartis Pharmaceuticals acquired Ciba-Geigy and began clinical trials. The first yielded dramatic results: 31 of 31 patients saw their white blood-cell counts return to normal. In about half of the patients, cells with the mutant 9;22 chromosome could no longer be detected. Patients in ongoing trials worldwide-including 60 patients in Larson's program at Chicago-have generally fared well, and the FDA approved Gleevec for treating CML in May. The medical center is also conducting trials of the pill for a usually intractable stomach cancer called gastrointestinal stromal tumor; in earlier trials Gleevec slowed tumor growth in more than half of patients and stopped growth in one out of four. More trials for leukemia, stromal tumors, and other cancers are under way nationwide. Questions remain, however. Will the cancer cells develop resistance to Gleevec? Must CML patients take the medicine all their lives?

Because basic research can take years or decades to bear fruit, Rowley says that as a scientist, "you have to believe in yourself, that what you are doing is important and really it's only a matter of time before its importance is recognized-and that people will then try to proceed to translate the observations you and others make into effective treatments for patients. I have to say I never expected to live to see this day. But I was fortunate, and here I am." Loecke appreciates that he is still here too. "I don't know how to repay all the people for what they've done for me," he says, referring to his nurses and doctors. But if he knew Gleevec's long story, he might thank Rowley, Abelson, and their colleagues too. - Cathy Shufro

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