ID #1060 Mechanism before medicine: defining chromatin-dependent vulnerabilities in high-risk medulloblastoma

Abstract

High-risk medulloblastoma remains one of the most lethal childhood brain tumours, with relapse largely incurable and survivors of current therapies experiencing significant long-term neurocognitive toxicity. While epigenetic therapies are increasingly entering clinical trials for paediatric brain cancers, their use has largely preceded a mechanistic understanding of how these agents impact fundamental tumour vulnerabilities, limiting rational patient selection and combination strategies.

In the high-risk medulloblastomas (p53-mutant sonic hedgehog (SHH) and Group 3 MYC-amplified) oncogenic transcription and epigenetic dysregulation significantly increase stress on DNA replication, creating a reliance on DNA repair and genome stability pathways for tumour cell survival. We hypothesise that chromatin regulators required to tolerate transcription-associated replication stress represent tractable therapeutic vulnerabilities that can be exploited to enhance existing treatments.

To investigate this, we performed a drop-out CRISPR-screen in cells challenged with replication stress and identified that chromatin and epigenetic regulators were core vulnerabilities. This included components of the SWI/SNF complex (SMARCA4/SMARCB1), BET family proteins (BRD2/BRD4) and cohesin (STAG2). We then pharmacological inhibited SWI/SNF with the preclinical therapeutic agent BRM014 in SHH-medulloblastoma DAOY cells and found and increase in genome stability and decreased proliferation. Further, we found that BRM014 treatment in combination with DNA-damage and replication stress inducing agent Etoposide was able to significantly reduce cell viability beyond Etoposide alone. Our on-going work continues to examine how this and other epigenetic agents interact with standard DNA-damaging therapies including cisplatin and gemcitabine, to induce synthetic lethality, and critically, why these combinations succeed or fail at a mechanistic level.

By directly linking chromatin regulation to genome stability and treatment response, this work provides a functional framework for rational combination therapy design. Rather than empirically advancing drugs into the clinic, this approach prioritises biological understanding to guide safer, more effective therapeutic strategies for children with high-risk medulloblastoma.