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    Pharmacological evaluation of the inhibition of polysialyltransferases as a therapeutic strategy in cancer. Characterisation of models for evaluating polysialic acid as a potential therapeutic target and pharmacological assessment of novel polysialyltransferase inhibitors

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    Publication date
    2013-09-20
    Author
    Al-Saraireh, Yousef M.J.
    Supervisor
    Shnyder, Steven D.
    Falconer, Robert A.
    Keyword
    Pharmacological models
    Chemotherapy
    Neuroblastoma
    Cancer
    Polysialyltransferases
    Neural cell adhesion molecule
    Polysialic acid
    Therapeutic strategy
    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    Institute of Cancer Therapeutics
    Awarded
    2012
    
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    Abstract

    Neuroblastoma is a highly metastatic and invasive tumour with poor prognosis. Despite recent advances in the treatment of neuroblastoma, mortality is still high due to uncontrolled metastatic disease, and novel therapeutic approaches for the treatment of neuroblastoma are therefore desperately needed. A potential novel approach for therapy of neuroblastoma relates to the polysialic acid decoration of the neural cell adhesion molecule (PSANCAM). PSA-NCAM is selectively re-expressed in a number of tumours including neuroblastoma, where it is thought to modulate tumour dissemination. Expression is strongly associated with poor clinical prognosis and an aggressive tumour phenotype. Inhibition of the enzymes responsible for synthesis of PSA, the polysialyltransferases (polySTs) presents a novel and selective therapeutic opportunity. The aims of the studies described in this thesis are to evaluate PSANCAM expression and function in neuroblastoma, and to develop and utilise cell-based models to pharmacologically investigate novel polyST inhibitors. PSA-NCAM was seen to be highly expressed in neuroblastoma clinical specimens and associated with phenotypes of tumour aggressiveness. A screening panel consisting of cell lines with a range of PSA-NCAM expression types was established and utilised to develop assays for pharmacologically assessing novel polyST inhibitors. Using cytidine monophosphate (CMP), a naturally-occurring inhibitor of polySTs, the robustness of the assays was confirmed before progression to evaluate novel molecules. From 16 compounds identified in an in vitro screen of polyST inhibition, three promising polyST inhibitors were identified. These promising polyST inhibitors modulated PSA-NCAM expression on the tumour cell surface and led to a significant reduction in cell migration. Therefore the work presented in this thesis suggests that targeting polySTs is a promising novel therapeutic strategy for neuroblastoma and further research in this area is warranted.
    URI
    http://hdl.handle.net/10454/5648
    Type
    Thesis
    Qualification name
    PhD
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