Researchers at the UNC Lineberger Comprehensive Cancer Center and their colleagues have developed a small molecule that selectively degrades a protein implicated in Ewing sarcoma, a rare and aggressive cancer of the bone and soft tissue that primarily affects children and teenagers. The preclinical study, published in the Journal of the American Chemical Society, points to a potential new therapeutic approach for a disease with limited treatment options when standard therapies fail.
Ewing sarcoma accounts for about 1% of childhood cancers in the United States, with roughly 200 new cases diagnosed annually, according to the American Cancer Society. Standard treatments often involve surgery, chemotherapy and radiation, but many tumors eventually develop resistance, leaving patients with few alternatives if the cancer returns.
Recent studies have identified the transcription factor ETV6 as a critical vulnerability in Ewing sarcoma cells.
Pengda Liu, PhD, associate professor of Biochemistry and Biophysics at UNC School of Medicine and UNC Lineberger, and a team of researchers have designed a novel therapeutic molecule, which they named d(GGAA)3s, that targets ETV6. This molecule belongs to a class of drugs known as transcription factor proteolysis targeting chimeras, or TF PROTACs, which are small compounds that co-opt the cell’s protein-degradation machinery to eliminate disease-driving proteins.
“After confirming ETV6’s essential role in Ewing sarcoma cell growth, we developed a TF PROTAC that selectively degrades ETV6 and suppresses tumor proliferation,” said Liu, one of the study’s corresponding authors.
The researchers developed d(GGAA)3s by linking (GGAA)3, a custom-made strand of DNA, with VHL ligands — molecules that bind to and interact with the VHL protein, which helps regulate gene expression and cell division. This configuration allows the molecule to recruit the ubiquitin-proteasome system to break down ETV6.
In lab studies, d(GGAA)₃s effectively reduced ETV6 levels in Ewing sarcoma cells without affecting EWS::FLI1, another fusion protein implicated in the disease. Interestingly, the compound appeared to increase EWS::FLI1 activity, leading to heightened cellular stress and tumor cell death.
“This enhanced stress made Ewing sarcoma cells more susceptible to chemotherapy, suggesting d(GGAA)₃s could be valuable in combination therapies,” Liu said.
Beyond Ewing sarcoma, the molecule also degraded ETV6 fusion proteins containing the ETS DNA-binding domain, suggesting broader potential against other ETV6-driven cancers, such as leukemia and lymphoma.
“This is the first therapeutic approach to directly target ETV6,” Liu said. “Our early results are encouraging, and we hope to translate these findings into clinical applications.”
Jian Jin, PhD, of the Icahn School of Medicine at Mount Sinai, was the paper’s co-corresponding author, and Zhichuan Zhu, PhD, a postdoctoral fellow in Liu’s lab, was the first author.
Authors and disclosures
This research was supported in part by the Andrew McDonough B+ Foundation Childhood Cancer Research Grant and the University Cancer Research Fund at the University of North Carolina.
A full list of authors and disclosures can be found in the published paper.