Molecular signature may identify cisplatin-sensitive breast tumors
- From: Matti Narkia <mna@xxxxxxxx>
- Date: Fri, 20 Apr 2007 04:49:58 +0300
Molecular signature may identify cisplatin-sensitive breast tumors
Protein interaction underlies treatment-resistant tumor, findings lead
to new clinical trial
BOSTON - April 19, 2007 - Researchers at the Massachusetts General
Hospital (MGH) Cancer Center have identified a subgroup of
hard-to-treat breast cancers that may be sensitive to the drug
cisplatin, rarely used in the treatment of breast tumors. They also
have discovered the molecular basis of this sensitivity, which may
help identify patients most likely to benefit from cisplatin
treatment. The findings will be tested in a clinical trial anticipated
to begin at the MGH Gillette Center for Breast Cancer and
collaborating institutions later this spring.
"This paper describes a specific molecular pathway that makes these
tumors sensitive to a therapy infrequently used for breast cancer,"
says Leif Ellisen, MD, PhD, of the MGH Cancer Center, senior author of
the study to appear in the May 2007 Journal of Clinical Investigation
and receiving early online release. "We're excited that this work has
led to the design of a clinical trial for women with a very difficult
to treat form of breast cancer."
About two thirds of breast cancers contain receptor molecules for the
hormones estrogen or progesterone, and in recent years antiestrogen
drugs like tamoxifen have improved outcomes for women with those
tumors. About 20 to 30 percent of tumors, some with hormone receptors,
have elevated levels of a growth-promoting protein called HER2, and
those tumors are candidates for treatment with the monoclonal antibody
Herceptin. The third major subtype is the 15 to 20 percent of breast
tumors that have neither estrogen nor progesterone receptors and also
do not overexpress HER2.
Since these so-called "triple-negative" tumors are treatable with
neither Herceptin nor antiestrogen drugs, the prognosis for patients
with the tumors has been poor. Triple-negative tumors are the most
common subtype found in patients with mutations in the BRCA1 gene, but
they also appear in women without alterations in the so-called "breast
cancer gene." There have been reports that BRCA1-associated,
triple-negative tumors might be sensitive to cisplatin, a drug used to
treat several other types of cancer, but whether the more common
sporadic triple-negative tumors shared that sensitivity was unknown.
The current study was designed to answer that question and to
investigate the mechanism underlying cisplatin sensitivity.
The research team focused on the function of p63, a protein that plays
a role in normal breast development and is related to the common tumor
suppressor p53. They analyzed tissue samples from triple-negative
breast tumors and normal breast tissues for the expression of several
forms of p63 and another related protein called p73, known to promote
the cell-death process called apoptosis.
The researchers found that a significant number of triple-negative
tumors overexpress particular forms of p63 and p73, a pattern not seen
in other types of breast cancers. Using an RNA interference system to
inhibit the action of p63, they showed that the protein stimulates
tumor growth by interfering with p73's normal ability to induce cell
death. Cisplatin was found to break up the binding of p63 to p73 and
reactivate the cell-death process.
"The most important finding was that, if the tumor cells did not
express both p63 and p73, the cells were not sensitive to cisplatin,"
says Ellisen. "These results suggest that testing p63 and p73 levels
in patients' tumors might help predict whether they would benefit from
cisplatin therapy." Ellisen is an assistant professor of Medicine at
Harvard Medical School.
The clinical trial to investigate the role of p63/p73 expression in
determining cisplatin sensitivity will be led by MGH researchers
through the Dana-Farber/Harvard Cancer Center. Starting in Boston in
the coming weeks, the trial will be open to patients with advanced
triple-negative breast cancer and eventually will be offered at other
U.S. cancer research centers. Patients or physicians interested in the
trial should call Karleen Habin at (617) 726-1922 and ask about the
cisplatin trial for breast cancer.
Additional authors of the Journal of Clinical Investigation paper are
first author Chee-Onn Leong, PhD; Nick Vidnovic, Maurice DeYoung, and
Dennis Sgroi, MD, all of the MGH Cancer Center. The study was
supported by grants from the Mary Kay Ash Charitable Foundation, the
National Institute of Dental and Craniofacial Research, the Tracey
Davis Memorial Fund, and the Avon Foundation.
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 nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Media Contact: Sue McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
Excerpted from
Molecular signature may identify cisplatin-sensitive breast tumors
<http://www.massgeneral.org/news/releases/041907ellisen.html>
--
Matti Narkia
.
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