March 27, 2003
Studies of Rare Blood Syndrome Uncover Novel Route to Cancer
By carefully studying why a rare blood disorder responds to the
anti-cancer drug Gleevec, researchers have discovered an entirely new
mechanism that generates cancer-causing genes.
The study, published in the March 27, 2003, issue of the New
England Journal of Medicine, shows that Gleevec is an effective
treatment for hypereosinophilic syndrome (HES), a blood disorder that
is nearly always fatal. According to the researchers, their studies
suggest that HES should be reclassified by the World Health
Organization from its current “gray-area” status as a
“syndrome” to a form of cancer.
“Nine of the eleven patients showed extraordinary and continuing responses to Gleevec treatment.”
D. Gary Gilliland
Senior authors of the article were D.
Gary Gilliland, a Howard Hughes Medical Institute investigator at
Brigham and Women's Hospital and Harvard Medical School, and Richard
Stone at the Dana-Farber Cancer Institute (DFCI). Joint first authors
on the paper were Jan Cools, a postdoctoral fellow in Gilliland's
laboratory, and Daniel DeAngelo, who is also at DFCI and an instructor
at Harvard Medical School.
HES is caused by overproliferation of a type of white blood cells
called eosinophils. Physicians treat the syndrome with a combination of
drugs and chemotherapy, said Gilliland, but eventually, the assault of
eosinophils damages major organs, and causes the heart or lungs to
fail, and ultimately results in death of most patients.
Recently, however, hints that the disorder might respond to Gleevec
began to crop up in the medical literature. “There was a report
of a single case of an HES patient treated with Gleevec and had what
was described as a miraculous response,” said Gilliland.
“This anecdotal report was substantiated by a group of
investigators that reported successful treatment in 4 of 5 additional
HES patients, reported in the The Lancet (a British
medical journal) last year.
Gleevec works by inhibiting enzymes called tyrosine kinases. When
the activity of tyrosine kinases is unregulated - which can occur when
chromosomes improperly exchange chunks of genetic material, creating
chromosomal rearrangements - cancer may develop.
With the apparent successes reported in the initial small case
studies, Gilliland, Stone and their colleagues decided to conduct their
own clinical trial and attempt a detailed study that they hoped would
reveal the underlying mechanism of HES. They enlisted the aid of
colleagues at eight medical centers who contributed 11 patients to the
study.
“Nine of the eleven patients showed extraordinary and
continuing responses to Gleevec treatment,” said Gilliland.
“Their eosinophilia just went away. In one case, a patient with
severe involvement of his central nervous system, in which he had lost
bowel and bladder function, completely recovered. It's stunning to see
such a recovery due to a simple pill that has minimal side effects
compared to conventional chemotherapy.”
According to Gilliland, the initial group of patients is still
responding to the drug, as have additional patients recruited after
submission of the New England Journal of Medicine article. In an
interesting twist, the researchers found that they could successfully
treat HES patients with doses of Gleevec that were lower than those
used to treat patients with chronic myelogenous leukemia. This is
significant, Gilliland said, in part, because Gleevec is very
expensive.
In the laboratory, the difficult work began when Gilliland and his
colleagues tried to find a molecular explanation for why the patients
responded to Gleevec therapy. “We didn't have any clues where to
look,” Gilliland said. “This is not an inherited disease,
so you cannot use the same strategies that one would use in familial
breast or colon cancer. There are no recurring chromosome abnormalities
that could reveal an underlying cause.”
Careful genetic analysis by Cools revealed some interesting
information: His work showed that a small deletion of DNA in a region
between two known genes could produce a tyrosine kinase that is
essentially “turned on” in the absence of a normal
activation signal. It appeared that in patients with HES, the absence
of a small amount of DNA created a fusion between two genes,
FIP1L1 and PDGFR alpha, which switches on PDGFR
alpha, a tyrosine kinase.
The researchers later confirmed that Gleevec did specifically block
the activity of the wayward kinase. They did this by analyzing the
genes of a patient who developed resistance to Gleevec due to an
additional mutation in the PDGR alpha gene— as well as by
analyzing the action of the drug in cell cultures.
“A key finding from this paper is this novel mechanism for
generating a gain-of-function fusion gene,” said Gilliland.
“This FIP1L1-PDGFR alpha fusion is a constitutively
activated tyrosine kinase, and it has all the hallmarks of a
cancer-causing tyrosine kinase.”
Until now, said Gilliland, genetic deletions were associated with
inactivation of tumor suppressor genes, an event that can also trigger
cancers. Discovery of this new mechanism may prompt researchers to take
a fresh look at whether it initiates other forms of cancer.
“These activated tyrosine kinases can act as gas pedals for
the tumors, as in acute myelogenous leukemia, breast cancers and
gastrointestinal stromal cell tumors,” said Gilliland. “Now
that we have one example where small deletions can activate these
kinases, we may find many more such examples of solid tumors with
activated kinases.
“Such a finding would be especially important therapeutically
because kinases are excellent drug targets. It's possible to make very
specific lock-and-key inhibitors like Gleevec that selectively block
kinase activity,” said Gilliland.
Although the broad range of standard analytical techniques now used
to detect cancer-causing abnormalities will not uncover such deletions,
said Gilliland, a screen of the 96 known tyrosine kinases in the human
genome could readily identify such deletions.
According to Gilliland, the new study also suggests that Gleevec may
be inhibiting other tyrosine kinases in some HES patients. While most
of the patients who were successfully treated did show the
characteristic gene fusion, four did not. Tracking down the causative
genetic abnormalities in these patients — as well as in those with
similar eosinophilic diseases — could yield additional insights into
the basis of Gleevec's effects, he said. Gilliland and his colleagues
are now exploring other kinase-inhibiting drugs to anticipate the
Gleevec resistance that the patients might well develop.
In addition to the treatment implications for HES patients, added
Gilliland, the findings offer an unequivocal diagnostic test for the
Gleevec-sensitive gene fusion.
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