�Using science lab and mouse models of human breast cancer, researchers have set up that a small molecule capable of targeting specific proteins on the surface of knocker 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 footpath. Lapatinib inhibits the activation of growth signaling proteins and their signaling pathways as well as cell migration and proliferation. Using the computer mouse model, the drug reduced the number of brain lesions that resulted from the injection of human cells. The study, which appeared on-line 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 seldom treated with drugs because many drugs do not cross the blood-brain barrier, a exceptional 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., straits 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 ar too large to slip by the blood/brain barrier to impact the cancer cells that have migrated to the psyche. 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 chest cancer occur in or so one-third of all cases of HER2-positive, metastatic bosom cancer. About 20 percentage to 25 percent of breast cancers are HER2-positive, meaning they have overly much of, or overexpress, the protein HER2 on their surface. These tumors tend to grow quicker and are more likely to recur than tumors that do not overexpress HER2.
Lapatinib inhibits the activation of both HER2 and the epidermal growth broker receptor (EGFR). Lapatinib in combination with the drug capecitabine has been sanctioned to treat patients with HER2-positive white meat 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 dose that blocks cell division).
"Lapatinib was well-tried in a human clinical study of brain metastases and showed only modest results," aforesaid Steeg. "However, we asked a different question. Rather than request 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 inquiry team injected human white meat 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 day-by-day for 24 days. When the researchers examined the mouse brains for metastatic breast cancer tumors, they found that lapatinib rock-bottom the development of large brain metastases by 50 percent or more compared to the placebo solution and that it also hit i 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 genus Cancer cells in the research lab. They set up that breast cancer cells that expressed more of the targeted receptors had greater predisposition to the drug. Those that explicit high levels of both EGFR and HER2 were approximately 30 percent more than sensitive to the growth inhibition personal effects of lapatinib than cells that expressed high levels of but one of these receptors. However, cells that only if expressed EGFR or HER2 were equally sensitive to the dose. The researchers also establish that lapatinib inhibited activation of the EGFR and HER2 proteins, as well as of proteins that are involved in cell signaling pathways that baffle gene expression, cell air division, and cellular telephone survival -- and which, ultimately, crataegus oxycantha contribute to the development of cancer.
"These findings point 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," aforesaid Steeg. Having completed their studies in the lab and in mice, the researchers expect 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 Optimization study, or ALTTO trial, which opened in 2008. This study was funded by NCI and the Department of Defense Breast Cancer Research Program.
Effect of lapatinib on the outgrowth of metastatic boob cancer cells to the brain.
Gril B, Palmieri D, Bronder JL, Herring JM, Vega-Valle E, Feigenbaum L, Liewehr DJ, Steinberg SM, Merino MJ, Rubin SD and Steeg PS.
Journal of the National Cancer Institute. Online July 29, 2008.
For more selective information on Dr. Steeg's research, please go here.
National Cancer Institute
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