27 October 2014

Stem Cell Cytotoxins against Brain Cancer

Genetically engineered stem cells Synthesize toxins that kill cancer cells

NanoNewsNet based on materials from Harvard Stem Cell Institute:
Scientists engineer toxin-secreting stem cells to treat brain tumors

Scientists at the Harvard Stem Cell Institute have developed a new way to use stem cells in the fight against cancerous brain tumors. A group led by neuroscientist Khalid Shah, MS, PhD, who had previously demonstrated the potential of stem cells loaded with the herpes virus that kills cancer cells, has now, with the help of genetic engineering, created stem cells capable of synthesizing and secreting tumor-destroying cytotoxins.

In an article in the journal Stem Cells (Stuckey et al., Engineering toxin-resistant therapeutic stem cells to treat brain tumors), Dr. Shah and his colleagues showed how cytotoxin-secreting stem cells can be used to completely destroy cancer cells remaining in the mouse brain after the removal of the main tumor. Such stem cells are implanted into the cavity left after the removal of the tumor, encapsulated in a biodegradable gel. This method solves the issue of delivery, which probably caused the failure of recent clinical trials of isolated cytotoxins delivered to the brain of patients.

"Cancer–killing toxins are already being used with great success in various forms of blood cancer, but they do not work as well in solid tumors, since these cancers are less accessible, and the toxins have a short half-life," explains Dr. Shah. "A few years ago, we realized that stem cells could be used to continuously deliver therapeutic toxins to brain tumors, but first we had to create genetically engineered stem cells that could resist these toxins themselves. Now we have toxin-resistant stem cells that can produce and secrete cancer-killing drugs."

Cytotoxins are deadly to all cells, but in the late 1990s, scientists learned to label them in such a way that they are absorbed only by cancer cells with certain surface molecules, which allows the toxin to be delivered to the cancer cell without posing a threat to its normal neighbors. Once inside the cell, the cytotoxin disrupts its ability to synthesize proteins, and, within a few days, the cell begins to die.

The stem cells developed by Dr. Shah avoid this fate because they carry a mutation that does not allow the cytotoxin to act inside the cell. In addition, the toxin-resistant stem cells have an additional genetic code that allows them to synthesize and secrete these substances. Cancer cells that encounter cytotoxins do not have such natural protection and therefore die. Dr. Shah and his group induced cytotoxin resistance in human neural stem cells, and then modified them so that they began to produce targeted toxins.

"We tested these stem cells on a clinically relevant mouse model of brain cancer by implanting them in gel–encapsulated form into the cavity remaining after tumor resection," Dr. Shah continues. "After doing all the molecular analyses and imaging to track the inhibition of protein synthesis in brain tumors, we really see that the toxins kill cancer cells and ultimately increase the survival of animals with brain tumor resection models."

Stem cells synthesizing cytotoxins encapsulated in a biodegradable gel (blue)
they help to kill brain cancer cells in the cavity left after its resection (green).
(Photo: Khalid Shah, MS, PhD)

In the near future, Dr. Shah plans to create a rational combination of toxin–secreting stem cells with a number of other therapeutic stem cells developed by his group to further improve the results of treatment of mouse models of glioblastoma, the most common brain tumor in people of mature age. Now researchers are seeking permission to conduct clinical trials of cellular approaches developed by them, which should be given by the FDA. According to Dr. Shah, clinical testing of his treatment methods may begin within the next five years.

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