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 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.
Delta-24-RGD was tested against the most aggressive brain tumor - glioblastoma multiforme, which originates in the glial cells that surround and support neurons. This tumor 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. Delta-24-RGD exploits the fact that a protein called retinoblastoma (Rb) is either missing or defective in brain tumors. Rb normally guards against both the proliferation of cancerous cells and against viral infection. So the virus has an easier time invading tumors and replicating in its cells. Adenoviruses attacking normal cells employ their own protein, E1A, to counteract retinoblastoma's defensive measures. To keep Delta-24-RGD out of normal cells, Fueyo and colleagues deleted a small part of the gene that produces E1A.
The research team 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."
"Our next experiments will address whether the cell kills itself or dies defending itself against the virus," Fueyo says. Sure, the cell dies either way, but the distinction is important, Fueyo says, because the virus could be redesigned to either fuel or block autophagy [self-cannibalization] to make it more effective. The autophagic protein Atg5 is heavily expressed in the dead tumor cells, making it a potential biomarker of the virus' effectiveness.
Illustration: Brain CT scan showing brain cancer. –Wikipedia.
The University of Texas M. D. Anderson Cancer Center (09/11/07)
RxPG News (09/11/07)
Science Daily (09/12/07)
Journal of the National Cancer Institute (Abstract, JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm102)