A new way to to use stem cells to fight brain cancer is revealed in a proof-of-concept study published in the journal Stem Cells, where scientists describe how they got the cells to produce and release toxins that kill only tumor cells.
Led by Dr. Khalid Shah, a neuroscientist at Harvard Stem Cell Institute, Harvard University, in Cambridge, MA, and also of Massachusetts General Hospital (MGH) in Boston, MA, the scientists found the toxin-releasing stem cells eliminated cancer cells left behind in mouse brains following tumor removal.
In recently published work, Dr. Shah showed how stem cells loaded with herpes can kill brain tumors. In this new study, he and his colleagues describe how they genetically engineered stem cells to make and secrete toxins that kill brain cancer cells without themselves being affected.
The toxins that the stem cells make are cytotoxins – they enter and kill cells within days by stopping their ability to make proteins, which prevents them growing, dividing and reproducing.
Cytotoxins are deadly to all cells, but in the late 1990s, scientists found a way to tag them so they only entered cancer cells with certain molecules on their surfaces. Normal cells without the surface molecules are unharmed.
Dr. Shah, who directs the Molecular Neurotherapy and Imaging Lab at MGH and Harvard Medical School, says:
“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.”
He and his colleagues put the stem cells inside a capsule of biodegradable gel that they deposited in the tumor site after removal. This appeared to overcome the problems of approaches that have tried to deliver purified cancer-killing toxins into patients’ brains – methods that have not succeeded in clinical trials.
The team is seeking federal approval for this and other stem cell techniques they have developed so they can proceed to clinical trial.
Dr. Shah explains that, a few years ago, they saw how stem cells could be used to provide a continuous supply of such therapeutic toxins to treat brain tumors, but the problem was how to do it without the toxins killing the stem cells themselves.
They eventually found a way to genetically engineer the stem cells so they did not succumb to the toxins they produced:
“Now, we have toxin-resistant stem cells that can make and release cancer-killing drugs,” he adds.
To accomplish this, they engineered human neural stem cells with a mutation that does not allow the toxin to act inside the cell. They also inserted a piece of genetic code so the stem cells can make and release tagged toxin that targets cancer cells.
When the toxin enters the target cancer cells, as they do not have the protective mutation, they eventually stop working and die. Dr. Shah explains how they tested this effect in mice:
“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.”
After doing all of the molecular analysis and imaging to track the inhibition of protein synthesis within brain tumors,” says Dr. Shah, “we do see the toxins kill the cancer cells and eventually prolonging the survival in animal models of resected brain tumors.”
The team now plans to bring together the results of experiments with toxin-releasing stem cells, and the different types of therapeutic stem cells they have developed, to refine their method in mice with glioblastoma, the most common brain tumor in human adults.
Dr. Shah expects to be starting clinical trials of the method within 5 years.
The study was funded by the National Institutes of Health and the James S. McDonnell Foundation.