Corresponding author Martine Roussel, PhD, St. Jude Department of Tumor Cell Biology, and first author Jake Friske, St. Jude Graduate School of Biomedical Sciences.
Efforts to develop effective therapies for MYC-amplified Group 3 medulloblastoma (G3-MB) are hindered by an incomplete understanding of how MYC expression is controlled in these tumors. MYC has long been considered “undruggable,” because it lacks clear pockets for drugs to bind and inhibit its activity. Scientists at St. Jude Children’s Research Hospital revealed that these tumors amplify MYC through extrachromosomal DNA (ecDNA) and identified a key enhancer located within tumor ecDNA that regulates its expression. The work was published today in Cancer Research.
G3-MB is a type of pediatric brain cancer associated with poor outcomes. It is largely driven by overexpression of MYC, a prominent oncogene that fuels rapid tumor growth. In many of these tumors, MYC is amplified on ecDNA — DNA that exists outside of chromosomes — and can rapidly replicate in number, allowing cancer cells to sustain high levels of oncogene expression. Current treatments for MYC-driven G3-MB remain limited in effectiveness because they do not specifically target the mechanisms driving MYC overexpression, a key factor behind the tumor’s behavior.
“Around 28% of cancers harbor oncogenes on extrachromosomal DNA, and many of these can be targeted with existing therapies,” said corresponding author Martine Roussel, PhD, St. Jude Department of Tumor Cell Biology. “But MYC has remained largely undruggable due to its disordered structure, making it difficult to target."
A new target for MYC-driven tumors emerges on ecDNA
Using 3D genome mapping, chromatin profiling and CRISPR screening, scientists identified a key regulatory enhancer, called ecMYC E1, located within tumor ecDNA that drives MYC expression specifically in MYC-amplified G3-MB. The enhancer exhibited key features of active regulatory elements and was shown to physically interact with the MYC promoter, revealing a previously unrecognized mechanism controlling oncogene activation.
Using advanced brain tumor organoid models, the researchers functionally characterized this enhancer and found that silencing it led to a significant reduction in MYC transcription, confirming that tumors rely on ecMYC E1 to sustain oncogene activity. These models faithfully maintain the genetic, epigenetic and cellular diversity of the original tumors, enabling the team to study MYC regulation within this unique context.
“This enhancer appears to be conserved across high-risk G3-MB and is specific to tumor cells, which gives us a potential way to target these tumors more precisely,” said Jake Friske, St. Jude Graduate School of Biomedical Sciences, who is completing his doctoral work in the Roussel laboratory. “In the future, that could help reduce the need for radiation or chemotherapy and limit long-term morbidity for patients.”
Tumors in which MYC is carried on ecDNA exhibit a unique ability to adapt to ecMYC E1 silencing. While turning off the enhancer initially lowers MYC levels, cancer cells adapt over time by increasing ecDNA copy number, thereby boosting MYC copy number and restoring gene expression. Because ecDNA can replicate independently of chromosomes, it enables this rapid compensation. In contrast, tumors with amplification of MYC within chromosomes do not show this adaptive response.
“If we target the enhancer alone, cells can become resistant by increasing ecDNA, but a combination therapy approach pairing enhancer silencing with treatments that block this increase in copy number, such as CHK1 inhibitors, offers a two-pronged way to limit tumor adaptation,” explained Friske.
The findings highlight a novel way to specifically target ecDNA in high-risk tumors, offering a potential strategy for treating a type of pediatric brain tumor in need of novel therapeutic approaches.
Authors and funding
The study’s other authors are Flore Cuisin, Paloma Guernalec, Stephanie Nance, Declan Bennett, Steven Burden, Ti-Cheng Chang, Hao Shi, Justin Williams, Virginia Valentine, Barbara Passaia, Bensheng Ju, Modupeore Adetunji, Paul Geeleher, Brian Abraham, Chunliang Li and Gang Wu, all of St. Jude; and Hayden Malone, St. Jude Graduate School of Biomedical Sciences.
The study was supported by grants from the National Cancer Institute (CA021765 and CA096832), American Cancer Society (RSG-DMC-135487), the Pediatric Cancer Dependencies Accelerator of the Broad Institute, the St. Jude Graduate School of Biomedical Sciences and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
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