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Sabnis, Durgagauri (2016) An investigation of druggable prognostic markers in paediatric ependymoma. PhD thesis, University of Nottingham.

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Abstract

Background: Paediatric ependymomas are the second most common malignant brain tumours in children. Tumour recurrence, chemoresistance and invasion of surrounding critical structures are the hallmarks of ependymomas. These features are consistent with the cancer stem cell (CSC) hypothesis which states that tumours harbour a sub-population of stem-like cells which underlie therapeutic resistance. This study investigates the role of the radial glial stem cell marker BLBP, the multidrug transporter ABCB1, and the DNA repair enzyme MGMT in therapy failure in ependymomas with particular emphasis on the role of CSCs.

Material and Methods: Database analyses were performed to assess the expression of the aforementioned markers in patients from 3 publicly available gene expression datasets. Furthermore, samples from 2 European paediatric ependymoma trial cohorts were screened for ABCB1, BLBP and MGMT expression by immunohistochemistry to elucidate their prognostic value. The expression of these markers was also determined in a panel of 5 ependymoma derived cell lines by QRT-PCR or western blotting analysis. Roles in chemoresistance (clonogenic & cytotoxicity assays) and tumour invasion (wound healing & 3D invasion assay) were then investigated.

Results: Poor survival in the chemotherapy-led paediatric ependymoma CNS9204 trial was significantly associated with ABCB1 (P=0.007) and BLBP (P=0.03) expression whilst MGMT (P<0.001) and BLBP (P=0.002) expression predicted poor survival in the radiotherapy-led CNS9904 trial cohort. ABCB1 and BLBP expression was consistent with the CSC hypothesis whilst MGMT was expressed in both CSCs as well as the tumour bulk. Inhibition of ABCB1 and BLBP, with the phosphodiesterase-5 inhibitor vardenafil and PPAR-ϒ antagonist GW9662 respectively, potentiated response to chemotherapy and also inhibited the ability of ependymoma cell lines to migrate and invade. Finally, whilst each of the tested cell lines were resistant to the alkylating agent temozolomide, they were sensitive to the novel N3-propargyl analogue of temozolomide.

Conclusion: ABCB1, BLBP and MGMT were not only markers of robust prognostic value but they also contributed functionally to the aggressive behaviour of ependymoma. Inhibition of ABCB1 and BLBP by vardenafil and GW9662 may represent effective approaches to overcome chemoresistance and invasion in ependymoma patients. The N3-propargyl analogue of temozolomide could also represent a novel treatment option for MGMT expressing ependymoma patients.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Coyle, E. Kerr, I.D.
Keywords:	Ependymoma, ABCB1, BLBP, MGMT
Subjects:	W Medicine and related subjects (NLM Classification) > WL Nervous system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	33243
Depositing User:	Sabnis, Durgagauri
Date Deposited:	19 Jul 2016 14:22
Last Modified:	07 Feb 2019 18:46
URI:	https://eprints.nottingham.ac.uk/id/eprint/33243

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