Novel Drug Screening Tool Could Lead to New Ewing Sarcoma Treatments

New technique uses chromatin as a way of identifying small molecule drugs for cancer.

A new screening technique has been found that tests thousands of potential drug compounds that could reverse the abnormal DNA unwinding found in Ewing sarcoma.

Ewing sarcoma is a cancer of the bone and soft tissue most commonly found in teens and young adults. In this disease, the cancer cell’s DNA is abnormally unwound from its usual condensed and compact state. Key genes are turned on once these sections of genetic code are open, which aids cancer cell growth.

A preclinical study was performed by researchers at the University of North Carolina Lineberger Comprehensive Cancer Center, with the results published in the Proceedings of the National Academy of Sciences journal.

Researchers noted the screening techniques are able to identify a group of compounds active in the Ewing sarcoma cell model. Furthermore, they believe the data from this drug screening strategy could be applied to a variety of cancers.

"This is exciting because we have identified an overall strategy for discovering new drugs based on the signature of how DNA is packaged," said researcher Ian J. Davis, MD, PhD.

Typically, patients with Ewing sarcoma have a DNA mutation in cancer cells that create a new gene called EWSR1-FLI1. Prior research conducted at UNC-Chapel Hill in 2012 found that EWSR1-FLI1 created a protein that traveled to surprising areas along the genome, causing it to unwind abnormally.

With this knowledge, researchers looked to develop a test that reflects the unique signature of DNA packaging within Ewing sarcoma. During the test, they studied sections of unwound chromatin in the cancerous cells only.

"There are characteristic regions where this oncogene goes in Ewing sarcoma to open up regions of DNA," Davis said. "So this offers us a unique signature for this cancer, one that is not observed in other cancers, creating an opportunity to use it in our new screen."

Using a specialized library at UNC-Chapel Hill Center that contained small molecule compounds, researchers tested hundreds of small molecules against their cellular model to determine whether or not the compound restored chromatin to its normal structure.

“The study's findings further validate the strategy of targeted drug discovery strategy,” said study co-author Stephen Frye, PhD. "We could go and screen small molecules to just try to kill cancer cells, but lots of compounds that will kill cells are not interesting or worthwhile to pursue as drugs. In this case, we're screening for activity of these drugs against a specific chromatin structural defect that we know is unique to Ewing sarcoma.”

The results of the study showed that a previous potential treatment for Ewing sarcoma called histone deactylase inhibitors were found to reduce chromatin accessibility at targeted sites.

"There is a huge, less explored class of compounds that we have designed to regulate chromatin," Frye said. "What's novel and interesting about our screening approach is we can test them without having to figure out every last detail about what goes wrong at a molecular level in Ewing sarcoma. We can simply say, we know there is a chromatin defect that's specific to this disease, and we have compounds that regulate chromatin, we can screen that set looking for a specific change in chromatin structure and then test active compounds for activity in models of cancer."

This strategy for targeting drugs leads to future testing of chromatin altering drugs in other cancers.

"We wanted to know if you can develop a screen that uses chromatin as a way of identifying small molecule drugs for cancer,” Davis said. “The answer is yes, you can. If we can get this to work in one disease that has a very distinct profile for how DNA is packaged, maybe we can get it to work to identify potential drugs in other cancers."