Jul 29 2008
Using laboratory and mouse models of human breast cancer, researchers have found that a small molecule capable of targeting specific proteins on the surface of breast cancer cells can inhibit the growth of breast cancer cells that migrate to the brain.
The small molecule used in the studies was the drug lapatinib (Tykerb), which disrupts an important breast cancer metabolic process called the Her2/neu signaling pathway. Lapatinib inhibits the activation of growth signaling proteins and their signaling pathways as well as cell migration and proliferation. Using the mouse model, the drug reduced the number of brain lesions that resulted from the injection of human cells. The study, which appeared online July 29, 2008, in the Journal of the National Cancer Institute, was conducted by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).
"Brain metastases are rarely treated with drugs because many drugs do not cross the blood-brain barrier, a special wall of blood vessels in the brain that prevents the passage of most foreign substances from the bloodstream into the brain and spinal cord," said Patricia S. Steeg, Ph.D., head of the Women's Cancers Section in NCI's Center for Cancer Research. "For example, Trastuzumab (Herceptin) is an FDA-approved antibody that targets HER2, and it can inhibit breast cancer's growth. These antibodies are too large to pass the blood/brain barrier to impact the cancer cells that have migrated to the brain. However, our mouse model suggests that lapatinib may successfully get across. If successful in humans, the drug may provide a new approach to treating brain metastases." Currently, treatment options for breast cancer patients with brain metastases are limited to steroids, radiotherapy, and surgery.
Brain metastases from breast cancer occur in approximately one-third of all cases of HER2-positive, metastatic breast cancer. About 20 percent to 25 percent of breast cancers are HER2-positive, meaning they have too much of, or overexpress, the protein HER2 on their surface. These tumors tend to grow faster and are more likely to recur than tumors that do not overexpress HER2.
Lapatinib inhibits the activation of both HER2 and the epidermal growth factor receptor (EGFR). Lapatinib in combination with the drug capecitabine has been approved to treat patients with HER2-positive breast cancer whose disease has progressed after treatment with trastuzumab in combination with certain other breast cancer therapies, including an anthracycline (a type of antitumor antibiotic) and a taxane (a drug that blocks cell division).
"Lapatinib was tested in a human clinical study of brain metastases and showed only modest results," said Steeg. "However, we asked a different question. Rather than asking lapatinib to melt a golf ball-sized metastasis in the brain, we asked if it would be more effective at preventing micrometastases, or small, undetectable metastases, from growing into large metastatic tumors."
To explore the effects of lapatinib on micrometastases, the research team injected human breast cancer cells that overexpressed EGFR only, or overexpressed both EGFR and HER2, into mice. Five days later, lapatinib or a placebo solution was administered twice daily for 24 days. When the researchers examined the mouse brains for metastatic breast cancer tumors, they found that lapatinib reduced the development of large brain metastases by 50 percent or more compared to the placebo solution and that it also hit one of its targets - it reduced the activation of HER2.
To gain a better understanding of how lapatinib was working, researchers investigated its effects on breast cancer cells in the lab. They found that breast cancer cells that expressed more of the targeted receptors had greater sensitivity to the drug. Those that expressed high levels of both EGFR and HER2 were approximately 30 percent more sensitive to the growth inhibition effects of lapatinib than cells that expressed high levels of only one of these receptors. However, cells that only expressed EGFR or HER2 were equally sensitive to the drug. The researchers also found that lapatinib inhibited activation of the EGFR and HER2 proteins, as well as of proteins that are involved in cell signaling pathways that regulate gene expression, cell division, and cell survival - and which, ultimately, may contribute to the development of cancer.
"These findings indicate that lapatinib may be beneficial in the treatment of patients with HER2-positive breast cancer who may have micrometastases and are thus at risk for the development of brain metastases," said Steeg. Having completed their studies in the lab and in mice, the researchers await the results of ongoing clinical trials of lapatinib where it is given in addition to the primary therapy, such as the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation study, or ALTTO trial, which opened in 2008. This study was funded by NCI and the Department of Defense Breast Cancer Research Program.
For more information on Dr. Steeg's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5851.