TOXIN SECRETING STEM CELLS TREAT BRAIN TUMORS , IN MICE
Harvard Stem Cell
Institute scientists at Massachusetts General Hospital have devised a new way
to use stem cells in the fight against brain cancer. A team led by
neuroscientist Khalid Shah, MS, PhD, who recently demonstrated the value of
stem cells loaded with cancer-killing herpes viruses, now has a way to
genetically engineer stem cells so that they can produce and secrete
tumor-killing toxins.
In the AlphaMed Press
journal Stem Cells, Shah's team shows how the toxin-secreting stem
cells can be used to eradicate cancer cells remaining in mouse brains after
their main tumor has been removed. The stem cells are placed at the site
encapsulated in a biodegradable gel. This method solves the delivery issue that
probably led to the failure of recent clinical trials aimed at delivering
purified cancer-killing toxins into patients' brains. Shah and his team are
currently pursuing FDA approval to bring this and other stem cell approaches
developed by them to clinical trials.
"Cancer-killing
toxins have been used with great success in a variety of blood cancers, but
they don't work as well in solid tumors because the cancers aren't as
accessible and the toxins have a short half-life," said Shah, who directs
the Molecular Neurotherapy and Imaging Lab at Massachusetts General Hospital
and Harvard Medical School.
"A few years ago
we recognized that stem cells could be used to continuously deliver these
therapeutic toxins to tumors in the brain, but first we needed to genetically
engineer stem cells that could resist being killed themselves by the
toxins," he said. "Now, we have toxin-resistant stem cells that can
make and release cancer-killing drugs."
Cytotoxins are deadly
to all cells, but since the late 1990s, researchers have been able to tag
toxins in such a way that they only enter cancer cells with specific surface
molecules; making it possible to get a toxin into a cancer cell without posing
a risk to normal cells. Once inside of a cell, the toxin disrupts the cell's
ability to make proteins and, within days, the cell starts to die.
Shah's stem cells
escape this fate because they are made with a mutation that doesn't allow the
toxin to act inside the cell. The toxin-resistant stem cells also have an extra
bit of genetic code that allows them to make and secrete the toxins. Any cancer
cells that these toxins encounter do not have this natural defense and
therefore die. Shah and his team induced toxin resistance in human neural stem
cells and subsequently engineered them to produce targeted toxins.
"We tested these
stem cells in a clinically relevant mouse model of brain cancer, where you
resect the tumors and then implant the stem cells encapsulated in a gel into
the resection cavity," Shah said. "After doing all of the molecular
analysis and imaging to track the inhibition of protein synthesis within brain
tumors, we do see the toxins kill the cancer cells and eventually prolonging
the survival in animal models of resected brain tumors."
Shah next plans to
rationally combine the toxin-secreting stem cells with a number of different
therapeutic stem cells developed by his team to further enhance their positive
results in mouse models of glioblastoma, the most common brain tumor in human
adults. Shah predicts that he will bring these therapies into clinical trials
within the next five years.
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