An imageable mouse model of brain-metastatic breast cancer has been developed by investigators at the Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute. They have shown the potential of a stem-cell-based therapy to eliminate metastatic cells from the brain and prolong survival. The study outlines an approach for averting the potential adverse impacts of stem cell therapy.
“Metastatic brain tumors account for about 30 per cent of advanced breast cancer metastases,” says Khalid Shah, MS, PhD, director of the Molecular Neurotherapy and Imaging Laboratory in the MGH Departments of Radiology and Neurology, who led the study. “The results offer an insight into how we may target brain metastases with stem-cell-directed molecules that prompt the death of tumor cells.”
The research team kicked off its search for novel, tumor-specific therapies that could hit multiple brain metastases without harming nearby tissues by developing a mouse model that closely mimicked what is seen in patients. That is the formation of many metastatic tumors all over the brain. Therapeutic options for such patients are currently very few, especially when there are a number of metastases.
The scientist bred a population of neural stem cells to express a potent version of a gene called TRAIL in their search for a potential new therapy. This particular gene codes for a molecule that activates receptors found on the surface of cancer cells that induce the death of healthy cells.
First the researchers verified in their model that the stem cells injected into the brain would travel only to multiple metastatic sites, leaving the tumor-free areas alone. Then they embedded TRAIL-releasing stem cells into the brains mice bearing metastasis. This action reduced the growth of tumors. Also, the results were even better when the TRAIL-spewing stem cells were injected into the carotid artery…it led to significantly slower tumor growth and increased survival.
For the stem-cell-based approach to be safe it is important to ensure that the engineered cells are eliminated from the brain at the end of the therapy. If they persist within the brain then they could damage normal tissue and possibly give rise to new tumors. To address this need the researchers doctored cells that other than TRAIL also release a viral gene which makes the engineered cells vulnerable to an antiviral drug called ganciclovir. It is proven that ganciclovir causes the death of HSV-TK-expressing stem cells.
Having tasted success with breast cancer metastases Shah and his team are now working on similar animal models for lung cancers and from melanoma.