A tailored virus destroys brain tumor stem cells that resist other therapies and cause lethal re-growth of cancer after surgery, a research team led by scientists at the University of Texas M. D. Anderson Cancer Center reports in the Sept. 18 edition of the Journal of the National Cancer Institute.
"We have shown first in lab experiments and then in stem cell-derived human brain cancer in mice, that we have a tool that can target and eliminate the cells that drive brain tumors," says co-senior author Juan Fueyo, M.D., associate professor in M. D. Anderson's Department of Neuro-Oncology. A request to launch a clinical trial of the virus, called Delta-24-RGD, is expected to go to federal regulators this month.
The virus was tested against the most aggressive brain tumor - glioblastoma multiforme, which originates in the glial cells that surround and support neurons. It is highly resistant to radiation and chemotherapy and so invasive that surgery almost never eliminates it. Patients suffering from this malignant glioma live on average for about 14 months with treatment.
Fueyo and colleagues developed Delta-24-RGD to prey on a molecular weakness in tumors and altered the virus so it could not replicate in normal tissue. They showed in a JNCI paper in 2003 that the virus eliminated brain tumors in 60 percent of mice who received injections directly into their tumors. The virus spreads in a wave through the tumors until there are no cancer cells left, then it dies.
Since 2004 scientists have found that brain tumors are driven by haywire stem cells that replicate themselves, differentiate into other types of cells, and bear protein markers like normal stem cells.
"Research has shown that these cancer stem cells are the origin of the tumor, that they resist the chemotherapy and radiation that we give to our patients, and that they drive the renewed growth of the tumor after surgery," Fueyo said. "So we decided to test Delta-24-RGD against glioma stem cells and tumors grown from them."
The research team led by Fueyo, co-senior author Frederick Lang, M.D., professor in M. D. Anderson's Department of Neurosurgery, and first author Hong Jiang, Ph.D., instructor in neuro-oncology, derived four brain tumor stem cell lines from four specimens of glioblastoma multiforme. All four lines exhibited the characteristics and protein signatures of stem cells. Delta-24 succeeded in killing all four types in the lab.
Next, the researchers grafted the stem cell lines into the brains of mice and treated the resultant tumors with injections of Delta-24-RGD. Untreated mice had a mean survival time of 38.5 days, while treated mice had a mean survival of 66 days. Two of the eight treated mice survived for 92 days, until the end of the experiment, with no neurological symptoms.
"It's important in animal models to see improvement in survival in the majority of animals, but to have some be cured and survive a long time without neurological symptoms is very rare," Fueyo said. "We have to be cautious, because an animal model doesn't fully represent humans, but the tumors grown by these stem cells closely resemble the tumors we see in our patients, which is an exciting finding in itself."
Tumors in other mouse models tend to be round and self-contained, explains co-senior author and Frederick Lang, M.D., professor in M. D. Anderson's Department of Neurosurgery. Malignant tumors in patients are never round, they invade other tissues and delve deeply into the brain. The cancer stem cell-derived tumors in these experiments have the irregular shape and invasive characteristics of their human counterparts.
"That similarity to the human tumor is encouraging," Lang said. "And it's also encouraging that we got basically the same results with Delta-24-RGD in this experiment that we got in our earlier experiment using other tumor models."