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Antisense Inhibits Ewing's Sarcoma in Mice

Antisense Inhibits Ewing's Sarcoma in Mice

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

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

"This shows that the abnormal fusion protein is responsible for the tumor progression," E. Shyam Reddy, PhD, associate professor, Jefferson Cancer Institute, said at the American Cancer Society Science Writers Seminar. The work was carried out in collaboration with 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 partly responsible for these malignancies, Dr. Reddy said. The fusion products from these translocations--chimeric proteins--function as transcriptional activators or sequestors, regulating the genes that ultimately bear the responsibility for tumorigenesis.

Cytogenic analysis in Ewing's sarcoma and related tumors reveals the characteristic translocation to be t(11;22) or t(21;22). Molecular analysis of these translocations shows that the 5´ region of the EWS gene (from band 22q12) is fused to the 3´ region of either the Fli-1 gene (from band 11q24) or erg gene (from band 21q22).

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

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

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