Investigating the RNA structurome of fusion-positive rhabdomyosarcoma (GREEND_U24CCLGMED)

Primary supervisor – Dr Darrell Green

Secondary supervisor – Prof Nicole Horwood

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma with ~2 per million new cases annually globally. RMS is a high-grade neoplasm of skeletal myoblast-like cells and mainly affects children under 10-years old but can occur in teenagers and adults. Risk stratification for children with RMS incorporates multiple clinical, pathological and molecular features that guide the appropriate clinical intervention. Standard of care in Europe for the highest risk cases, i.e. metastatic RMS, comprises systemic ifosfamide, vincristine and actinomycin D plus local therapy (surgery/radiotherapy) where feasible. Despite this highly invasive treatment protocol, three-year event free and overall survival is 35% and 48%, respectively. These numbers are significantly below the combined childhood cancer five-year survival rates of 84% (UK), 81% (EU) and 85% (US). RMS is therefore a cancer of unmet need where better understanding and treatment improvements will disseminate internationally.

Around 25% of all RMS cases harbour a chromosomal translocation involving chromosomes 1 or 2 with chromosome 13, which is associated with a worse prognosis when compared to RMS cases without a fusion. Fusion-positive RMS (FPRMS) patients share the same driver mutation (PAX3/7::FOXO1), but unlike most other cancers there are relatively few other somatic alterations. Despite this modest genetic architecture, FPRMS is a clinically heterogenous disease.

Cellular RNAs, including those from the PAX3/7::FOXO1 fusion, are heterogeneous with respect to their alternative processing, subcytoplasmic location and secondary (and hence tertiary) structures, but the functional importance of this complexity is poorly understood. This PhD project will interrogate the RNA structurome of FPRMS. PAX3/7::FOXO1 mRNA structures will be investigated in cell lines, xenograft mouse models and human clinical samples. RNA isoforms will be linked with the clinical phenotype and molecular mechanisms (e.g. microRNA binding, RNA binding protein interactions, RNA decay, etc.) will be investigated. This new information will be used to inform the development of RNA structure-modifying drugs, which target RNA structural motifs linked with a poorer patient outcome. These medicines are on the horizon so this project has extremely timely potential.

Entry requirements

The minimum entry requirement is 2:1 in Biological Sciences, Molecular Genetics, Molecular Biology, Biochemistry.

Mode of study

Full-time

Start date

1 October 2024