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Gene mutations predict which lung cancers
will respond to Iressa
MGH finding should improve cancer
treatment, lead to new targeted therapies
BOSTON - April 29, 2004 - Researchers from the Massachusetts
General Hospital (MGH) Cancer Center have discovered a molecular
marker that identifies lung cancer patients whose tumors will respond
to treatment with the drug Iressa (gefitinib). Their findings, which
will be published in the May 20 New England Journal of Medicine,
are being released online today to coincide with the online release
by Science of related research from Dana-Farber Cancer Institute.
"This discovery will help us significantly improve the treatment
of many lung cancer patients and is also an important next step
in the molecular targeting of cancer drugs," says Daniel Haber,
MD, PhD, director of the MGH
Cancer Center and senior author of the NEJM paper. "We're
hopeful that what we have learned will eventually lead to more new
drugs that will target tumor-specific mutations without affecting
normal tissues."
Iressa was approved a year ago for the treatment of advanced non-small-cell
lung cancer (NSCLC), a tumor that is particularly difficult to treat
and is the leading cause of cancer deaths in the U.S. In a major
clinical trial Iressa caused tumors to shrink significantly in only
13.6 percent of patients, but some of those responses were rapid
and dramatic. As a result, the FDA approved the drug because there
are no other treatment options for NSCLC patients for whom standard
chemotherapy has failed.
Iressa acts by disabling the epidermal growth factor receptor (EGFR)
on the surface of lung cancer cells, halting a sequence of signals
that can lead to the uncontrolled growth characterizing a malignant
tumor. In their search for an answer to why the drug worked so well
for some NSCLC patients but was of no assistance to others, the
MGH team screened tumor samples from MGH patients who participated
in the Iressa clinical trial to search for mutations in the EGFR
gene.
Initial analysis found mutations affecting the same area (the ATP
cleft of the kinase domain) of the receptor protein in eight of
nine patients that had responded to Iressa, but no EGFR mutations
were seen in tumors from seven patients who did not respond. In
addition, many of the patients whose tumors responded to Iressa
were of a subtype of NSCLC called bronchoalveolar cancer. Subsequently
the researchers analyzed samples from 25 other NSCLC patients who
had not been treated with Iressa. Two of those samples had mutations
identical to ones found in Iressa-responding patients, and they
were both bronchoalveolar tumors. Many samples from several other
types of cancer were also studied, but none had similar EGFR mutations,
indicating that they only are important in a particular subset of
cancers.
To determine the effect of these mutations, the MGH team developed
cultures of cells expressing two of the mutated receptor proteins.
Compared with cells expressing the normal receptor, those with mutant
EGFR responded much more powerfully to addition of growth factor,
with a two- to three-fold increase in activation. In addition, receptor
activation persisted six times longer in the mutant receptors than
in cells with normal receptors.
Since most of the mutations identified in this study affect the
area of the receptor targeted by Iressa, the researchers measured
receptor activation in cells treated with various doses of the drug.
They found that the mutated receptors were 10 times more sensitive
to being inhibited by Iressa than were normal receptors.
"Understanding these mutations has helped us define the molecular
basis of a type of lung cancer that relies on a particular signalling
pathway which can be blocked," says Haber, a professor of Medicine
at Harvard Medical School (HMS). "In addition, these mutations
are unprecedented in that they increase proliferation of tumor cells
while simultaneously making them more sensitive to drug treatment."
Thomas Lynch, MD, director of the MGH
Thoracic Oncology Center and a co-lead author of the NEJM paper,
says, "These findings will help determine which patients will
benefit from Iressa and which should not receive it. In addition,
if we know that a patient is likely to respond, we might be able
to start treatment earlier with this drug that is more effective
and has fewer side effects than standard chemotherapy." Lynch
is an HMS associate professor of Medicine.
While there is currently no commercial test to screen tumor samples
for this mutation, the MGH researchers are working to insure rapid
development of a test based on this discovery, for which a patent
has been applied. They also are setting up clinical trials of treatment
plans based on screening for the identified EGFR mutations and hope
to initiate studies involving treatment of early-stage tumors and
as an adjunct to surgical tumor removal. Additional follow-up studies
could help develop similarly targeted therapies against other tumors.
The report's other lead authors are Daphne Bell, PhD, and Raffaella
Sordella, PhD, of the MGH Cancer Center. Additional co-authors are
Sarada Gurubhagavatula, MD, Ross A. Okimoto, Brian W. Brannigan,
Patricia L. Harris, Sara M. Haserlat, Jeffrey G. Supko, PhD, Frank
G. Haluska, MD, PhD, David N. Louis, MD, David C. Christiani, MD,
and Jeff Settleman, PhD, also of the MGH Cancer Center. The study
was supported by grants from the National Institutes of Health,
the Doris Duke Charitable Foundation, the Sandler Family Foundation,
the Cole-Angelus Fund, Romaine Fund, and Sue's Fund for Lung Cancer
Research.
The MGH Cancer Center is the largest provider of cancer care in
New England and is a member of Dana-Farber/Harvard Cancer Center,
which coordinates research collaborations throughout HMS.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
For information on potential clinical trials based on this research,
call 617 724-7829 or send e-mail to mghonctl@partners.org.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
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