Cancer researchers hit a bullseye with new drug target for Ewing sarcoma


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Fluorescent staining shows how PARP and CDK12 inhibitors combine to deal a lethal blow to Ewing sarcoma. In the top row, green represents locations of DNA damage incurred by Ewing sarcoma cells. In the bottom row, red represents DNA repair activity. Together, PARP and CDK12 inhibitors lead to Ewing sarcoma cell death.
Credit: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center

Screening a class of recently-developed drug compounds — so-called “CDK inhibitors” capable of blocking CDK7/12/13 proteins — against hundreds of different human cancer cell lines, researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have found that CDK12 inhibitors pack a particularly lethal punch to Ewing sarcoma, a rare cancer typically affecting children and young adults.

“No one has previously considered CDK12 inhibition as a way to combat Ewing sarcoma,” says Kimberly Stegmaier, MD, senior author of the new Cancer Cell paper that describes the findings.

In 2014, Nathaneal Gray, PhD, co-author on the new paper, and his team were the first to develop CDK inhibitors.

“Now, in mice, we’ve shown that Ewing sarcoma cells die if CDK12 is knocked out genetically or chemically inhibited,” Stegmaier says. What’s more, her team has discovered that CDK12 inhibition can be combined with another drug, called a PARP inhibitor, to double down on Ewing sarcoma cells.

The revelation that CDK12 inhibition can kill Ewing sarcoma cells brings a surge of hope to the field of pediatric oncology, which has long been challenged to find new drugs against childhood cancers.

“Pediatric cancers often involve abnormalities in genes that encode for transcription factors, shapeshifting proteins that bind to DNA sequences to activate or repress gene expression,” says Stegmaier, who co-directs the pediatric hematologic malignancy program at Dana-Farber/Boston Children’s and is a member of the Broad Institute’s Cancer Program. “Due to their disordered physical structure, transcription factors have largely eluded drug discovery efforts.”

A molecular view of Ewing sarcoma

In Ewing sarcoma, the second-most common bone cancer in children and adolescents, an error involving two genes gives rise to an abnormal fusion transcription factor called EWS/FLI. Once produced, EWS/FLI wreaks havoc by tripping the switch of normally quiet regions of DNA, turning on genes that are supposed to stay off, while also turning off genes that should be active.

Cancer researchers call EWS/FLI a “pioneer factor” for its ability to turn on genes that wouldn’t be expressed otherwise.

“In Ewing sarcoma and other cancers involving transcription factor fusion ‘onco-proteins’ like EWS/FLI, these mutated transcription factors drive abnormal cell behavior and tumor growth,” Stegmaier explains. “EWS/FLI has so far not been able to be targeted by conventional drug chemistry.”

But now, Stegmaier and her team may have unleashed a workaround to disarming EWS/FLI-expressing tumor cells via CDK12, a readily-targetable enzyme. After their wide-ranging drug screen revealed a potential link between CDK12 inhibition and Ewing sarcoma, the team sought to understand why.

“CDK12 is known to be important for gene regulation, so we wondered why the EWS/FLI fusion protein might engender sensitivity to CDK12 inhibitors,” Stegmaier says…

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This article and images were originally posted on [Latest Science News — ScienceDaily] January 26, 2018 at 11:31AM. Credit to Author and Latest Science News — ScienceDaily | ESIST.T>G>S Recommended Articles Of The Day

 

 

 

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