Antisense Inhibits Ewing's Sarcoma in Mice

NEW ORLEANS--A novel therapy, based on antisense RNA technology,targets aberrant fusion products produced by chromosomal translocationsand may lead to the loss of tumorigenicity in tumor cells of theEwing's sarcoma family, a study from Thomas Jefferson Universityhas shown.

Nude mice were injected with either a Ewing's sarcoma cell linemanipulated by antisense RNA technology that inhibited the expressionof these fusion proteins, or a control transfected tumor cellline. In mice receiving the antisense-treated cell line, tumorgrowth was suppressed by up to 90%, compared with controls.

"This shows that the abnormal fusion protein is responsiblefor the tumor progression," E. Shyam Reddy, PhD, associateprofessor, Jefferson Cancer Institute, said at the American CancerSociety Science Writers Seminar. The work was carried out in collaborationwith Dr. Veena N. Rao, assistant professor, Jefferson Cancer Institute.

Recent investigations of human solid tumors have revealed that,as with the leukemias, chromosomal translocations may be partlyresponsible for these malignancies, Dr. Reddy said. The fusionproducts from these translocations--chimeric proteins--functionas transcriptional activators or sequestors, regulating the genesthat ultimately bear the responsibility for tumorigenesis.

Cytogenic analysis in Ewing's sarcoma and related tumors revealsthe characteristic translocation to be t(11;22) or t(21;22). Molecularanalysis of these translocations shows that the 5´ regionof the EWS gene (from band 22q12) is fused to the 3´ regionof either the Fli-1 gene (from band 11q24) or erg gene (from band21q22).

Dr. Reddy said that these translocations give rise to aberrantchimeric proteins by fusion of two normal proteins. These EWS-Fli-1and EWS-erg chimeric proteins are the transcriptional activatorsthat can be targeted in an effort to suppress the cell's tumorigenicity.Antisense RNA technology was used to specifically inhibit theexpression of these aberrant EWS-fusion proteins.

"Eventually, we may be able to develop therapeutic drugsto recognize the fusion products versus normal ones and thereforeinhibit fusion functions. If you destroy the fusion product, thecells lose their cancerous properties," Dr. Reddy commented.