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
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
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.