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September 18, 2007

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Tailored virus kills brain cancer cells in mice

Sept. 11, 2007
Courtesy M. D. Anderson Cancer Center
and World Science staff

A cus­tomized vi­rus in a mouse study killed stem cells that cause an ex­tremely ag­gres­sive, te­na­cious brain can­cer, re­search­ers re­port.

Sci­en­tists at the Un­ivers­ity of Tex­as M. D. An­der­son Can­cer Cen­ter in Hous­ton, Tex­as an­nounced the find­ings in the Sept. 18 is­sue of the Jour­nal of the Na­t­ional Can­cer In­sti­tute.
The vi­rus “can tar­get and elim­i­nate the cells that drive brain tu­mors,” by es­sen­tially forc­ing them to eat them­selves, said study co-author Juan Fue­yo. The re­search­ers said they ex­pect to sub­mit a re­quest to launch a clin­i­cal tri­al of the vi­rus, called Delta-24-RGD, this month.

They tested the vi­rus against the most ag­gres­sive brain tu­mor, glioblas­toma mul­ti­forme, which orig­i­nates in spe­cial­ized cells known as glia, Fue­yo said. Glia sur­round and sup­port neu­rons, the brain cells that con­duct elec­tri­cal sig­nals. 

Glioblas­toma mul­ti­forme re­sists radia­t­ion and chem­o­ther­a­py treat­ments and is so in­va­sive that sur­gery al­most nev­er elim­i­nates it, Fue­yo and col­leagues said. Pa­tients suf­fer­ing from this ma­lig­nan­cy live on av­er­age for about 14 months with treat­ment.

The re­search­ers de­vel­oped the vi­rus to ex­ploit a weak­ness in tu­mors but leave nor­mal tis­sue un­harmed. They found in a 2003 study 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 out-of-control stem cells, a type of “mas­ter cell” ca­pa­ble of de­vel­op­ing in­to a va­ri­e­ty of oth­er cell types, the re­search­ers said. Even when sur­gery de­stroys a tu­mor, the rogue stem cells can pro­duce a new one.

Fueyo’s team grafted four dif­fer­ent lin­eages of the stem cells in­to mouse brains and treated the re­sult­ant tu­mors with in­jec­tions of the vi­rus. Un­treated mice sur­vived 38.5 days on av­er­age, and treated mice 66 days, they re­ported. But two of the treated ones lived for 92 days, un­til the end of the ex­pe­ri­ment, with no neu­ro­lo­g­i­cal symp­toms.

“An an­i­mal mod­el does­n’t fully rep­re­sent hu­mans,” Fueyo cau­tioned. “But the tu­mors grown by these stem cells closely re­sem­ble the tu­mors we see in our pa­tients, which is an ex­cit­ing find­ing in it­self.” Usu­al­ly, tu­mors ar­ti­fi­cially in­duced in lab an­i­mals don’t mim­ic real tu­mors very well, he re­marked—but these did, sprawl­ing out and deeply in­vad­ing oth­er brain ar­eas be­fore the vi­rus beat them back.

The vi­rus ex­ploits the fact that a mol­e­cule called retinoblas­toma is mis­sing or de­fec­tive in brain tu­mors. The mol­e­cule nor­mally guards against both the pro­lifera­t­ion of can­cerous cells and against vi­ral in­fec­tion. So the vi­rus, a mem­ber of a family of vi­ruses called adenovi­ruses, has an eas­i­er time in­vad­ing tu­mors and repli­cat­ing in its cells. 

Adenovi­ruses at­tack­ing nor­mal cells nor­mally em­ploy a mol­e­cule called E1A to coun­ter­act the retinoblas­toma de­fense. So to keep the vi­rus out of nor­mal cells, Fueyo and col­leagues ex­plained, they simply needed to de­lete a small part of the vi­ral gene that pro­duces E1A. The vi­rus forc­es tu­mor cells to de­vour them­selves un­til they die, a form of self-cannibal­iz­a­tion called au­to­phagy, they wrote.

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A customized virus in a mouse study killed stem cells that cause an extremely aggressive, tenacious brain cancer, researchers report. Scientists at the University of Texas M. D. Anderson Cancer Center in Houston, Texas announced the findings in the Sept. 18 issue of the Journal of the National Cancer Institute. The virus “can target and eliminate the cells that drive brain tumors,” by essentially forcing them to eat themselves, said study co-author Juan Fueyo. The researchers said they expect to submit a request to launch a clinical trial of the virus, called Delta-24-RGD, this month. They tested the virus against the most aggressive brain tumor, glioblastoma multiforme, which originates in specialized brain cells known as glia. Glia surround and support neurons, cells that conduct electrical signals and are considered the brain’s main information-transmitting units. Glioblastoma multiforme resists radiation and chemotherapy treatments and is so invasive that surgery almost never eliminates it, Fueyo and colleagues said. Patients suffering from this malignancy live on average for about 14 months with treatment. The researchers developed the virus to exploit a weakness in tumors but leave normal tissue unharmed. They found in a 2003 study 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 out-of-control stem cells, a type of “master cell” capable of developing into a variety of other cell types, the researchers said. Even when surgery destroys a tumor, the rogue stem cells can produce a new one. “These cancer stem cells are the origin of the tumor,” Fueyo said. His team grafted four different lineages of these stem cells into mouse brains and treated the resultant tumors with injections of the virus. Untreated mice survived 38.5 days on average, and treated mice 66 days, they reported. But two of the treated ones lived for 92 days, until the end of the experiment, with no neurological symptoms. “An animal model doesn’t fully represent humans,” Fueyo cautioned. “But the tumors grown by these stem cells closely resemble the tumors we see in our patients, which is an exciting finding in itself.” Usually, tumors artificially induced in lab animals don’t mimic real tumors very well, he remarked—but these did, sprawling out and deeply invading other areas of the brain before the virus beat them back. The virus treatment exploits the fact that a molecule called retinoblastoma is either missing or defective in brain tumors. The molecule normally guards against both the proliferation of cancerous cells and against viral infection. So the virus, a member of a family of viruses called adenoviruses, has an easier time invading tumors and replicating in its cells. Adenoviruses attacking normal cells normally employ a molecule called E1A to counteract the retinoblastoma defense. So to keep the virus out of normal cells, Fueyo and colleagues explained, they simply needed to delete a small part of the viral gene that produces E1A. The virus forces tumor cells to devour themselves until they die, a form of self-cannibalization called autophagy, they wrote.