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Exploring the therapeutic potential of protein tyrosine phosphatase inhibition in neuroblastoma

Irving, Elsa; (2019) Exploring the therapeutic potential of protein tyrosine phosphatase inhibition in neuroblastoma. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Neuroblastoma accounts for 15% of paediatric cancer deaths and there is an urgent need for improved therapeutic strategies. Phosphotyrosine signalling, regulated by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs), is critical for virtually all aspects of cell behaviour, and is commonly perturbed in cancer. We have previously shown that pan-inhibition of PTPs using oxidovanadium induces cytotoxicity in a panel of neuroblastoma cell lines. We therefore hypothesise that there exist specific PTPs that promote tumour cell survival, and that their specific or pan-inhibition may be beneficial for the treatment of neuroblastoma. Whilst promising preclinical data using vanadium-derived compounds in in vitro and in vivo models of cancer has been reported, clinical trials have been prevented in part due to concerns surrounding off-target tissue toxicity. I have taken several approaches to harness the cytotoxic properties of oxidovanadium, and PTP inhibition, with the aim to develop new therapeutic strategies for neuroblastoma. The tumour-promoting roles of specific PTPs were investigated using loss-of-function approaches including RNAi and CRISPR/Cas9 gene knockout. The dual specificity phosphatase CDC14B was identified as a potential candidate, although further validation studies need to be considered for this enzyme to be taken forward as a potential therapeutic target. In a parallel study, the first genome-wide transcriptomic analysis in neuroblastoma cells treated with oxidovanadium has revealed a potential role for cAMP signalling in bismaltolato oxidovanadium (BMOV)-induced cytotoxicity. This pathway and others that are affected by oxidovanadium may be a source of useful therapeutic targets for neuroblastoma in the future. Finally, I have shown for the first time that hydrophobic oxidovanadium can be packaged into liposomes and maintains its cytotoxicity when delivered to neuroblastoma cells. This presents a novel opportunity to deliver vanadium with potentially fewer safety concerns, whilst retaining its broad activity and high levels of anti-cancer efficacy.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Exploring the therapeutic potential of protein tyrosine phosphatase inhibition in neuroblastoma
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/ 4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10071151
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