Translational Research in Rhabdomyosarcoma
Section: Section of Paediatric Oncology
This research area is carried out in collaboration with JM Shipley, D Williamson, E Missaglia, Section of Molecular Carcinogenesis, J Anderson, Institute of Child Health and A Kelsey & B Guertl-Lackner, Dept Paediatric Pathology, Manchester Children's Hospital.
Rhabdomyosarcoma is an embryonal skeletal muscle cancer that occurs in young children and in adolescents. There is already a known molecular marker associated with the alveolar subtype and a worse clinical outcome. This is the reciprocal balanced chromosomal translocation, t(2p36;13q32) which fuses the PAX3 gene on chromosome 2 to the Forkhead related gene, FKHR (FOXO1A) on 13q32. Previous work in the team of Dr Janet Shipley has shown the presence of several regions of amplification of genetic material mainly in alveolar rhabdomyosarcoma (particularly 2p24, 13q31). These have been analysed further by comparative expressed sequence hybridisation (CESH) and array comparative genomic hybridisation (CGH). This has defined the smallest region of gain and identified overexpressed genes whose clinical and biological relevance is now being pursued. A retrospective collection of tumours from patients enrolled in the previous national clinical trials (MMT 89, 95 and 98) is underway to allow comprehensive analysis of the presence of the PAX3-FOXO1A fusion gene and its variants, alongside comprehensive immunohistochemical studies of relevant biological pathways on tissue arrays.
Edoardo Missaglia salary and consumables are funded by the Chris Lucas Trust
Drug discovery for rhabdomyosarcoma
Investigators: K Pritchard-Jones, J Renshaw, O Slater; in collaboration with JM Shipley, E Missaglia, D Williamson, Section of Molecular Carcinogenesis; P Workman, W Aherne, R Orr (Section of Cancer Therapeutics)
We are investigating the cytotoxicity of novel biological agents in rhabdomyosarcoma cell lines that are well characterized for a range of molecular abnormalities associated with prognosis. Efficacy is evaluated in relation to the presence of known or putative molecular targets for these novel agents in primary tumour samples. Part of this work is within a European consortium for Innovative Therapies for Children with Cancer (ITCC). In parallel, we have begun a high-throughput screen for compounds showing activity against alveolar rhabdomyosarcoma bearing the characteristic PAX3-FOXO1A fusion gene.
Edoardo Missaglia salary and consumables are funded by the Chris Lucas Trust
Cancer Genome Project (Paediatric Component)
Investigators: D Hargrave, K Pritchard-Jones; in collaboration with M Stratton, R Wooster, A Futreal, Section of Cancer Genetics; Wellcome Trust Sanger Institute, Hinxton
We are collaborating with the Cancer Genome Project team at the Sanger Centre to ensure that paediatric cancer is well represented in this exciting initiative to identify novel cancer genes. Paediatric cancer is not well represented in the public cell line repositories. Hence we have assembled a collection of more than 150 paediatric cancer cell lines from individual international sources. These have now been screened for homozygous deletions and for mutations in both known and novel cancer genes. Initial results have confirmed known areas of loss of heterozygosity (LOH) and demonstrated several new regions of LOH in a variety of tumour types. Evaluation of the role of each gene in primary cancers is being analysed on samples collected through the auspices of the UK Children's Cancer Study Group (UKCCSG) national tumour bank.
External Funding: Cancer Research UK, Wellcome Trust
In the Section of Paediatric Oncology
