Ewing sarcoma is an aggressive pediatric cancer that is most commonly caused by the improper fusion of the gene EWS with the gene FLI1. Though the cause has long been known, therapeutic targeting of this fusion has, to date, proven very difficult.
A recent study looked downstream from this fusion to discover other links in the chain of events that leads to cancer. This fusion sets microRNA-22 in motion, which regulates another gene, KDM3A, and this signaling chain helps ensure that the outcome of the EWS/FLI1 fusion is cancer. Researchers from the University of Colorado (CU) Cancer Center in Aurora suggest that these new targets may provide more easily druggable alternatives to the EWS/FLI1 fusion itself. The study was recently published in Oncogene (2013; doi:10.1038/onc.2013.541f).
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“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.
This study highlights the complex cascade of events that cause cancer. Even in seemingly “simple” cancers like Ewing sarcoma with known oncogenic drivers, cancer-causing action tends to depend on a cascade of events the oncogenes initiate. Therefore, oncogenes may sit at the head of long, complex strings of cellular events, all of which are needed to cause cancer.
In this study, Jedlicka and colleagues used another form of ribonucleic acid (RNA) called small hairpin RNA (shRNA) to mute the expression of the tumor-promoting gene KDM3A. But Jedlicka pointed out that, in general, although shRNA is an extremely useful tool in the laboratory, its use as a therapeutic agent is thus far limited.
“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.
However, because KDM3A has an enzymatic activity—it modifies the cell’s genetic material to affect how other genes are expressed—it could potentially be targeted with small-molecule inhibitors, similar in structure to many drugs currently in use. Such inhibitors could theoretically be taken in pill form and would be able to cross into cancer cells where they could inhibit tumor growth. Importantly, genetic studies in model organisms suggest that KDM3A is not needed in most normal cells, so it’s possible that its targeting could be well tolerated as a therapy.
In addition, early data suggests that KDM3A may be a more common tumor promoter, so it may have application in many cancers.
This article originally appeared on ONA
