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RNA Silencing in Paediatric Cancer
Many paediatric cancers originate from aberrant human development, rather than accumulated DNA damage typical of adult malignancies. Endogenous in utero mutagenic events are a likely source for cancer-inducing mutations in paediatric cancers. At the molecular level, paediatric tumours commonly exhibit differentiation arrest, epigenetic dysregulation and genome rearrangement, which produces broad transcriptional alterations and greater transcriptomic diversity than seen in adult cancers. The Green lab applies molecular and computational approaches to study post-transcriptional gene regulation in paediatric sarcomas, aiming to uncover mechanisms of metastasis and identify potential therapeutic targets.
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Group Leader: Dr Darrell Green
View my research profileI am the scientific group leader for RNA research at Norwich Medical School. I first trained as a biomedical scientist at Addenbrooke’s Hospital in Cambridge before completing my PhD at the University of East Anglia with a focus on microRNA and bone cancer. I undertook postdoctoral training at UEA expanding on this work, developing single-cell RNA sequencing in circulating tumour cells, before setting up my own group in 2018.
Please get in touch regarding PhD research opportunities
Bone Sarcoma
Metastasis is the leading cause of cancer-related death. While primary tumour analyses have illuminated mechanisms of tumorigenesis and clonal evolution, fatal metastases remain poorly understood. Improved diagnostics have increased 5-year overall survival, but metastatic relapse after initial good response to new therapies is frequent. Our research started with studying the molecular biology that underpins metastasis. Early work looked at the role of small RNAs in disease progression and identified oncogenic roles for microRNAs (e.g. miR-140) and tumour suppressor roles for tRNA-derived fragments (e.g. tRNAGlyTCC) plus their interactions with RNA-binding proteins (e.g. YBX1). More recently, we have focused on circulating tumour cells, i.e. the “seeds” of metastasis, and their fundamental biology at single-cell resolution, which drives the spread of cancer around the body. We identified novel gene regulatory networks (e.g. MAPK7/MMP9) that dictate tumour-immune interactions causing metastasis. We also discovered that metastatic cells could generate functional non-coding RNAs not observed in normal or even tumour cells, accessing the “dark genome” to enable disease spread.
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RNA STRUCTURE IN GENE REGULATION
Ewing sarcoma (EwS) and fusion-positive rhabdomyosarcoma (FP-RMS) are driven by gain-of-function gene fusions, most commonly EWSR1::FLI1 in EwS and PAX3::FOXO1 in FP-RMS. In EwS, the EWSR1::FLI1 oncoprotein governs two reversible cellular states, a proliferative “high” state and a migratory “low” state. These states have been inferred from gene signatures, as the fusion mRNA is often barely detectable, suggesting regulation may occur at the translational or structural RNA level. RNA folding, shaped by ions, RNA-binding proteins and post-transcriptional modifications, underpins transcript stability and function. Our work investigates how aberrant RNA structure and its regulation contributes to metastasis in EwS and FP-RMS, aiming to uncover RNA-mediated mechanisms that could be exploited therapeutically.
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CADD522 DRUG DEVELOPMENT
Paediatric sarcomas, including Ewing sarcoma, osteosarcoma and rhabdomyosarcoma are treated with chemotherapy and surgery, yet outcomes remain poor and treatment-related morbidity is high. More effective, less toxic targeted therapies are urgently needed. We identified RUNX2, a transcription factor essential for in utero development, as an oncogenic driver reactivated in paediatric sarcomas. Because transcription factors lack conventional drug-binding pockets, computer-aided drug design was used to develop CADD522, a small-molecule inhibitor that blocks RUNX2-DNA interaction. In xenograft sarcoma models, CADD522 potently suppressed RUNX2 target gene expression and significantly improved progression-free and overall survival without detectable toxicity. We are now developing CADD522 towards first-in-human readiness.
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Recent Publications
Targeting metastasis in paediatric bone sarcomas
Bull et al. (2025) – Molecular CancerBayesian unsupervised clustering identifies clinically relevant osteosarcoma subtypes
Llaneza-Lago et al. (2024) - Briefings in Bioinformatics
Green et al. (2024) – Clinical Cancer Research
YBX1-interacting small RNAs and RUNX2 can be blocked in primary bone cancer using CADD522
Green et al. (2023) – Journal of Bone Oncology Rated Most Popular Paper in JBO 2023-2025
Ball et al. (2023) – Journal of Bone and Mineral Research Selected as the March 2023 issue Front Cover