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Under the Microscope: Precision Tools Bring New Insights for Pediatric Cancer

Although the outlook for many children with cancer has improved significantly over the past several decades, there is great need for new treatments that will eradicate cancer more effectively and with fewer side effects—so kids with cancer can get back to just being kids.

But when it comes to childhood cancers, developing new therapies often requires a unique approach. With adult cancers, researchers can sometimes take advantage of cancer-causing genetic mutations that are linked to sensitivity to specific drugs. This strategy is more difficult to apply to pediatric cancers because these cancers are usually driven by very few mutations.

Miguel Rivera, M.D., from Massachusetts General Hospital aims to design new therapies for pediatric cancers by uncovering the biological mechanisms behind them. In particular, his research focuses on how gene expression programs are altered in cancer. His recent work has centered on a pediatric bone cancer, known as Ewing sarcoma that is caused by a single mutation that directly leads to changes in gene expression.

“It’s critical that we understand how pediatric cancers, such as Ewing sarcoma, work to be able to create therapies that are going to be effective and not cause side effects,” said Rivera. “We now have very precise molecular tools that can help us gain new insights into the mechanisms that drive cancer cells.”

Editing gene regulation

Ewing sarcoma is caused by a single genetic event known as a chromosomal translocation, which brings together two genes from separate chromosomes to form a fusion protein called EWS-FLI1. This fusion protein changes how certain genes are expressed in a way that leads to cancer.

With V Foundation funding, Rivera used state-of-the-art approaches to test the effects of EWS-FLI1 at specific locations in the genome where this fusion protein binds. To do this, Rivera used a new technology that leverages the breakthrough gene editing tool CRISPR to perform what is called epigenome editing. The technique allows researchers to pinpoint a specific part of the genome and change its activation state to see how it affects gene expression. For example, by turning an EWS-FLI1 binding site off, it is possible to determine its precise contribution to gene expression.

“Developing this new experimental approach so that it could be applied to Ewing sarcoma was technically challenging,” said Rivera. “However, we were successful in using it to inactivate locations where EWS-FLI1 is binding.”

Possible clues for therapies

Using epigenome editing, the researchers have directly shown that individual EWS-FLI1 binding sites are powerful enhancers that control the expression of target genes from a large distance. Some of these genes could represent new drug targets, because they are likely important for tumor growth. The information gained from epigenomic editing studies could also be used to find ways to directly impair the function of EWS-FLI1 at the locations where it binds.

“This was a high-risk project,” said Rivera. “The support of the V Foundation was instrumental in getting these new tools up and running and applying them to study Ewing sarcoma.”

What’s more, the team is now joining forces with other scientists to continue to build on its progress. “The data we gathered helped us to become part of an NIH consortium grant that links us with other researchers studying Ewing sarcoma,” said Rivera.

The researchers are now working to apply what they’ve learned to develop new experimental treatments, while also delving deeper into the function of EWS-FLI1 and its target genes. Ultimately, they hope the work will lead to gentler and more effective therapies—and more smiles for patients and their families.