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Title: Characterisation of potential therapeutic molecules for neuroblastoma using chick chorioallantoic membrane xenograft model
Author: Swadi, Rasha
ISNI:       0000 0004 7658 6837
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Neuroblastoma is a paediatric cancer derived from the sympathoadrenal cell lineage that commonly presents as a high-risk metastatic disease with a poor prognosis. Currently, differentiation therapy with retinoic acid is an effective therapeutic option used in the clinic, however not all tumours respond. New therapeutic agents that can control not only tumour growth but also metastasis are urgently needed and drugs that promote differentiation are particularly appropriate for neuroblastoma treatment. Preclinical models are required to aid the development of novel therapeutics for this challenging childhood malignancy, however current systems are complex and inherently costly. Here we employ a 3Rs-compliant cost-effective preclinical chick embryo model to act as a tool for neuroblastoma therapeutic research. Neuroblastoma cell lines were engrafted on the chorioallantoic membrane (CAM) of chick embryos and allowed to form tumours over a 7 day period. If cells were preconditioned in hypoxia they metastasised into the chick embryo. First, we validated the chick embryo model using retinoic acid and then investigated the potential of CDK inhibitors on neuroblastoma cell differentiation, tumour progression and metastasis. With retinoic acid and the CDK inhibitors we observed a reduction of tumour cell proliferation and an increase in differentiation markers. The CDK inhibitors were particularly effective in inhibiting metastasis with a single injection reducing the number of embryos with metastasis by 60%. In addition, the expression of a panel of genes with known roles in metastasis, which increased upon hypoxia-preconditioning, was largely reduced by RO-3306 (CDK1 inhibitor). These results demonstrate that CDK inhibitors are a promising alternative to currently existing therapies. We have also begun to establish the chick embryo model as an alternative to the mouse xenograft model for short term analysis of cell differentiation, proliferation, apoptosis and metastasis in response to drug therapy.
Supervisor: Moss, Diana ; Campbell, Barry ; Kalirai, Helen ; Coupland, Sarah Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral