Molecular signature may identify cisplatin-sensitive
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
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
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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