decades of molecular research, a cancer drug leaves the lab -
Rowley's 1972 discovery paved the way for a leukemia-targeting
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.
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.
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.
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.
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
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.
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
was very little interest in this outside the community that studied
chromosomes," she recalls. She herself did not know where the
discovery might lead.
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.
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
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."
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.
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?
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