The Investigation of Targets for Therapy in Brain Tumours
Kinsella, Paula (2011) The Investigation of Targets for Therapy in Brain Tumours. PhD thesis, Dublin City University.
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Gliomas are among the most difficult of tumours to treat. Their highly invasive
nature leads to recurrence even after aggressive therapy including surgery,
radiotherapy and chemotherapy. A promising target for new therapies are tyrosine
kinases, because they regulate a large range of proteins involved in growth,
metabolism and differentiation. The receptor tyrosine kinases, epidermal growth
factor receptor (EGFR), platelet derived growth factor receptor (PDGFR) and C-Kit,
as well as the non-receptor tyrosine kinase C-Abl are often amplified,
overexpressed, and/or mutated in gliomas and play an important role in glioma
development. A number of tyrosine kinase inhibitors (TKIs) have been developed
and tested in clinical trials with mixed results.
In collaboration with Beaumont hospital 31 glioma cell cultures were
established to identify molecular markers indicative of responsiveness to EGFR and
PDGFR blockade. Each culture was characterised with regard to their protein
expression profile, their proliferative and invasive behaviour and their
responsiveness to three TKIs, erlotinib, gefitinib and imatinib, and two
chemotherapy drugs, docetaxel and temozolomide.
All data of 26 high-grade gliomas (20 primary glioblastomas, 2 secondary
glioblastomas, and 4 grade III astrocytomas including medical history of the patients
were analysed using hierarchical clustering analysis (HCA) and principal component
analysis (PCA) employing multivariate statistics.
Two distinct clusters of samples were found, which separated by the
expression of PTEN and PDGFR-a in cluster 1 and predominately PDGFR-b,
EGFR, phosphorylated C-Kit (p-C-Kit) and phosphorylated C-Abl (p-C-Abl)
expression in cluster 2. Principal components analysis of the culture data captured
55% of the variance in the dataset showing PTEN, PGDFR-a and PGDFR- loading
vectors in approximately the same direction.
Imatinib responsiveness was strongly correlated with high expression levels
of PTEN and PDGFR-a. Responsiveness to erlotinib was correlated with the lack of
expression of all proteins tested, while non-responders showed higher expression of
PTEN and PDGFR-a. Responders to gefitinib fit into two groups, the majority
(group 1) were influenced by the expression of the proteins tested, while the second
smaller group correlated with the lack of protein expression. Non-responders to
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