Combination treatment stymies breast cancer growth in mice
- From: Matti Narkia <mna@xxxxxxxx>
- Date: Thu, 10 May 2007 17:08:56 +0300
Baylor College of Medicine News Release:
Combination treatment stymies breast cancer growth
<http://www.bcm.edu/news/item.cfm?newsID=867>
Combination treatment stymies breast cancer growth
HOUSTON -- (May 1, 2007) -- A combination of three different
drugs that block the HER-2 receptor, a critical cellular growth
signal for some breast cancers, eradicated aggressive breast
tumors in mice and could point the way toward developing better
treatments in patients, said researchers from the Breast Center
at Baylor College of Medicine in a report that appears today in
the Journal of the National Cancer Institute.
"For the first time, we were able to cure mice of a very
aggressive human breast tumor," said Dr. Rachel Schiff, assistant
professor in the Breast Center at Baylor College of Medicine and
senior author of the report.
In prior such studies, treatment only slowed or delayed the
growth of tumors, she said. In this case, the tumors disappear
and do not come back, even when treatment is stopped.
The treatment involved is a new approach known as "targeted"
therapy because the protein (in this case, HER-2) driving a tumor
to grow is first identified in a patient's tumor and then
specific drugs are used to block that particular growth pathway
in the cells, said Dr. C. Kent Osborne, director of the Breast
Center and the Dan L. Duncan Cancer Center at BCM. He is also an
investigator on the study.
"When you go after a specific target in a patient's tumor, the
treatment is likely to be more effective and less toxic," said
Schiff.
The tumors in question ? nearly 25 percent of all breast cancers
? have high levels of HER-2. While the HER-2 makes the tumors
more aggressive, it also provides a target against which new
drugs can act.
Previously, treatment for patients with HER-2 positive tumors was
less effective.
"Now we have effective treatment, and survival is markedly
improved," said Dr. Grazia Arpino, lead investigator of the study
and a postdoctoral fellow at BCM.
"These tumors are initially highly sensitive to a drug known as
trastuzumab or Herceptin, one of the drugs used in combination in
the mouse study and which is approved by the FDA (U.S. Food and
Drug Administration) for treatment," said Schiff.
However, the tumor is wily and can sometimes escape the drug's
effects, resulting in resistance. Adding two other experimental
drugs ? gefitinib and pertuzumab -- that inhibit HER-2 in
different ways can more completely block the growth signals in
the tumor, causing it to die.
In one of the tumors studied in this report, blocking the
stimulatory effects of estrogen on the tumor was also necessary
for optimal treatment, said Schiff. Completely blocking the HER
pathway is critical, she said. Leaving out just one of the three
drugs was much less effective.
A clinical study using drug combinations in newly diagnosed patients
with HER-2 positive breast cancer will start soon under the direction
of physicians at BCM's Breast Center, said Osborne.
"We are very excited to see if our laboratory results can be
translated to patients with the more aggressive types of breast
cancer," he said.
Others who participated in the research include Carolina Gutierrez,
Heidi Weiss and Mothaffar Rimawi of BCM, Suleiman Massarweh, now of
the University of Kentucky, Lavina Bharwani now of Johns Hopkins
Singapore International Medical Center in China, and Sabino De Placido
of Universita di Napoli Federico of Naples, Italy.
Funding for this research comes from the National Institutes of
Health, The Jacqueline Seroussi Memorial Foundation for Cancer
Research and the Susan G. Komen for the Cure (previously Susan G.
Komen Breast Cancer) Foundation.
-----------------------------------------------------------------
The reference for the study is
Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L, De
Placido S, Osborne CK, Schiff R.
Treatment of human epidermal growth factor receptor 2-overexpressing
breast cancer xenografts with multiagent HER-targeted therapy.
J Natl Cancer Inst. 2007 May 2;99(9):694-705.
PMID: 17470737 [PubMed - in process]
<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17470737>
<http://jnci.oxfordjournals.org/cgi/content/full/99/9/694> (free full
text)
Abstract:
"BACKGROUND: Human epidermal growth factor receptor 2 (HER2)
is a member of the HER signaling pathway. HER inhibitors
partially block HER signaling and tumor growth in preclinical
breast cancer models. We investigated whether blockade of all
HER homo- and heterodimer pairs by combined treatment with
several inhibitors could more effectively inhibit tumor
growth in such models. METHODS: Mice carrying xenograft
tumors of HER2-overexpressing MCF7/HER2-18 (HER2-transfected)
or BT474 (HER2-amplified) cells were treated with estrogen
supplementation or estrogen withdrawal, alone or combined
with tamoxifen. One to three HER inhibitors (pertuzumab,
trastuzumab, or gefitinib) could also be added (n > or = 8
mice per group). Tumor volumes, HER signaling, and tumor cell
proliferation and apoptosis were assessed. Results were
analyzed with the t test or Wilcoxon rank sum test and
survival analysis methods. All statistical tests were two-
sided. RESULTS: Median time to tumor progression was 21 days
for mice receiving estrogen and 28 days for mice receiving
estrogen and pertuzumab (difference = 7 days; P = .001;
hazard ratio [HR] of progression in mice receiving estrogen
and pertuzumab versus mice receiving estrogen = 0.27, 95%
confidence interval [CI] = 0.09 to 0.77). Addition of
gefitinib and trastuzumab to estrogen and pertuzumab
increased this time to 49 days (difference = 21 days; P =
.004; HR of progression = 0.28, 95% CI = 0.10 to 0.76).
MCF7/HER2-18 tumors disappeared completely and did not
progress (for > or = 189 days) after combination treatment
with pertuzumab, trastuzumab, and gefitinib plus tamoxifen
(19 of 20 mice) or plus estrogen withdrawal (14 of 15 mice).
Both combination treatments induced apoptosis and blocked HER
signaling and proliferation in tumor cells better than any
single agent or dual combination. All BT474 tumors treated
with pertuzumab, trastuzumab, and gefitinib disappeared
rapidly, regardless of endocrine therapy, and no tumor
progression was observed for 232 days. CONCLUSION: Combined
treatment with gefitinib, trastuzumab, and pertuzumab to
block signals from all HER homo- and heterodimers inhibited
growth of HER2-overexpressing xenografts statistically
significantly better than single agents and dual
combinations."
--
Matti Narkia
.
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