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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
Al-Saraireh, Yousef M.J.
Al-Saraireh, Yousef M.J.
Publication Date
2012
End of Embargo
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Rights
The University of Bradford theses are licenced under a Creative Commons Licence.
Peer-Reviewed
Open Access status
Accepted for publication
Institution
University of Bradford
Department
Institute of Cancer Therapeutics
Awarded
2012
Embargo end date
2027-03-05
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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.
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Type
Thesis
Qualification name
PhD
Notes
The full text will be available at the end of the extended embargo period: 5th March 2027