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Tailored virus kills brain cancer cells in mice


Posted on: 09/12/2007

Tailored virus kills brain cancer cells in mice

Sept. 11, 2007
Courtesy M. D. Anderson Cancer Center

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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