Vanderbilt-Ingram Cancer Center scientists have reported a successful "one-two punch" against breast cancer in cell and animal studies using two targeted therapies that interfere with a key growth signal pathway.
The findings, reported last month in the journal Cancer Research, provide the foundation for a clinical trial in patients with metastatic breast cancer that produces too much of a protein called HER2/neu. This protein is the target for the antibody Herceptin.
Like the laboratory work, the clinical trial will combine Herceptin with another drug called ZD1839, or Iressa, that targets the epidermal growth factor receptor (EGFR), also known as HER1. The HER network transmits signals that lead to the overgrowth of cells that characterizes cancer.
In the laboratory, the researchers found that they could indirectly inhibit the activity of HER2 by directly inhibiting HER1. They also observed a greater rate of tumor cell death and greater tumor reduction by combining Herceptin and Iressa than by using either inhibitor alone.
"Both Herceptin and Iressa have minimal side effects," said Dr. Stacy L. Moulder, assistant professor of Medicine (Hematology/Oncology), lead author of the journal paper and principal investigator of the clinical trial. "We’re hopeful that we’ll be able to use these drugs together to shrink tumors with fewer side effects."
Therapies that specifically target steps in the cancer development process are generating a great deal of excitement among clinicians, scientists and patients. The Food and Drug Administration has approved two such treatments for cancer so far – Herceptin for a portion of breast cancer patients and Gleevec for a form of leukemia. However, many more including Iressa are being investigated against various types of cancer.
Although these drugs appear to provide great specificity with fewer side effects than traditional chemotherapy, there are many unanswered questions, including whether the body will develop resistance. Many researchers, including Moulder and her colleagues, caution that cancer is such a complex disease, attacking it at multiple points may be necessary for longterm success.
This study is the first demonstration of a combined molecular approach to inhibit the HER network in breast tumor cells that overexpress HER2. (HER2 is overexpressed in about a third of human breast cancers).
"It is conceivable that the combination exerts a more effective or sustained inhibition of survival signals up-regulated by the HER signaling network," the authors wrote in the Dec. 15 issue of Cancer Research, adding that further investigation is needed to fully explain this "supra-additive" anti-tumor effect. "Nonetheless, these results suggest that simultaneous blockade of different molecular sites within the HER network may diminish potential compensatory mechanisms by tumor cells."
The clinical trial will ultimately enroll 150 patients with HER2-overexpressing metastatic breast cancer. Some of the participants will be women whose disease has progressed after treatment with chemotherapy. Others will be women who have advanced disease and have refused standard treatment, instead preferring to go straight to the investigational therapy.
The trial is what’s known as a Phase I/Phase II investigation. The Phase I portion will examine two dose levels, in three patients each, to make determine what if any side effects result from combining the drugs. If the combination is found to be safe, the trial will be expanded into a Phase II study to test effectiveness.
Molder’s Vanderbilt co-authors were F. Michael Yakes, Ph.D., research instructor in Medicine (Hematology-Oncology); Dr. Robert Bianco of the Department of Medicine; Dr. Jean F. Simpson, associate professor of Pathology; and Dr. Carlos Arteaga, Ingram Professor of Cancer Research, professor of Medicine (Hematology-Oncology) and Cancer Biology.
The National Institutes of Health, the Department of Veteran Affairs, the Vanderbilt-Ingram Cancer Center and the American Association for Cancer Research supported the research. The Eastern Cooperative Oncology Group of the National Cancer Institute funds the ongoing clinical trial.
Materials provided by Vanderbilt University Medical Center. Note: Content may be edited for style and length.
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