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 tumours.

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 tumours amplify MYC through extrachromosomal DNA (ecDNA) and identified a key enhancer located within tumour ecDNA that regulates its expression.

The work was published today in Cancer Research. G3-MB is a type of paediatric brain cancer associated with poor outcomes.

It is largely driven by overexpression of MYC, a prominent oncogene that fuels rapid tumour growth. In many of these tumours, 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 tumour’s behaviour.

“Around 28% of cancers harbour oncogenes on extrachromosomal DNA, and many of these can be targeted with existing therapies,” said corresponding author Martine Roussel, PhD, St. Jude Department of Tumour Cell Biology. “But MYC has remained largely undruggable due to its disordered structure, making it difficult to target.”

A new target for MYC-driven tumours emerges on ecDNA

Using 3D genome mapping, chromatin profiling and CRISPR screening, scientists identified a key regulatory enhancer, called ecMYC E1, located within tumour 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 MYCpromoter, revealing a previously unrecognised mechanism controlling oncogene activation.

Using advanced brain tumour organoid models, the researchers functionally characterised this enhancer and found that silencing it led to a significant reduction in MYC transcription, confirming that tumours rely on ecMYC E1 to sustain oncogene activity.

These models faithfully maintain the genetic, epigenetic and cellular diversity of the original tumours, 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 tumour cells, which gives us a potential way to target these tumours 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.” Tumours 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, tumours 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 tumour adaptation,” Friske said.

The findings highlight a novel way to specifically target ecDNA in high-risk tumours, offering a potential strategy for treating a type of paediatric brain tumour in need of novel therapeutic approaches.

Article: A Conserved Enhancer Locus in Extrachromosomal DNA and Homogeneously Staining Regions Activates MYC Transcription in Group 3 Medulloblastoma

Source: St. Jude Children's Research Hospital