Researchers from the University of Colorado (CU) Cancer Center have found that the gene KDM3A, which is expressed due to misfiring of the genes EWS and FLI1, could be a new therapeutic target for Ewing’s sarcoma. Ewing’s sarcoma is an aggressive cancer that occurs in children. The most common cause of the disease has long been known to be the misfiring of EWS/FLI1 genes, however, targeting these genes has proven difficult. The findings were been published in Oncogene (2013; doi:10.1038/onc.2013.541f).
“We started with all the microRNAs downstream from the EWS/FLI1 fusion and narrowed in on microRNA-22. But then we looked even further downstream from there and found that microRNA-22 works through another gene, KDM3A, to cause this cancer. When we turned down this gene (KDM3A) in lab studies, we observed a profound inhibition of the tumorigenic properties of Ewing Sarcoma cells,” said Paul Jedlicka, MD, PhD, of the CU Cancer Center.
Jedlicka and colleagues successfully used small hairpin ribonucleic acid (shRNA) to silence the expression of KDM3A. However, more time is needed to study shRNA before use as a therapeutic drug in humans. “We can design shRNA to silence nearly any chosen gene, but then in cell studies we use a virus to carry this shRNA inside cells. There are a number of challenges to this approach in humans,” Jedlicka said.
KDM3A has an enzymatic activity which modifies the genetic materials in cells, so researchers believe that it could be inhibited by other silencing agents such as small molecule inhibitors, which are already used in many drugs in the form of pills. Notably, KDM3A is found not to be necessary in most cells in genetic studies, so it is expected that therapy targeting KDM3A could be well-tolerated or cause less adverse events.