)
RNA Silencing in Paediatric Cancer
Cancer remains the leading cause of death by disease in children and young adults. A major reason is the intrinsic ability of some paediatric cancers to become resistant and relapse, even after an initially successful response. Once relapse occurs, therapeutic options are scarce, and survival rates remain dismal. Unlike adult cancers, paediatric tumours harbour few mutations, suggesting they evolve through cellular plasticity rather than genetic diversification. Arising during development from inherently plastic cells, they retain the ability to switch phenotypes without altering DNA, enabling rapid, reversible transitions into metastatic and drug-tolerant states. The Green lab applies molecular and computational approaches to investigate such transcriptional diversity and non-genetic evolution in paediatric bone sarcomas, aiming to identify potential therapeutic targets.
)
)
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
THE BIOLOGY OF BONE SARCOMAS
While primary tumour analyses have illuminated mechanisms of tumorigenesis, fatal metastases remain poorly understood. 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), and their interactions with RNA-binding proteins (e.g. YBX1). We developed new techniques to investigate circulating tumour cells, i.e. the “seeds” of metastasis, and their fundamental biology at single-cell resolution. This work identified gene regulatory networks (e.g. MAPK7 and MMP9) that dictate tumour-immune interaction and metastatic outcome. More recently, we have discovered that metastatic cells can generate functional non-coding RNAs not observed in normal or even tumour cells, accessing their so-called “dark genome” to enable disease spread.
)
RNA STRUCTURE IN GENE REGULATION
Ewing sarcoma (EwS) is driven by gain-of-function FET::ETS gene fusions, most commonly EWSR1::FLI1, encoding a pioneer transcription factor that creates de novo enhancers at repetitive GGAA DNA microsatellites. The EWSR1::FLI1 oncoprotein governs two reversible cellular states, a proliferative “high” state and a migratory “low” state. These phenotypes have been inferred from gene signatures because the fusion mRNA transcript 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, aiming to uncover RNA-mediated mechanisms that could be exploited therapeutically.
)
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 and classically known for controlling osteoblast and chondrocyte differentiation, as a master regulator of sarcoma plasticity. 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-binding. 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.
)
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