Glioblastoma multiformae is an aggressive form of astrocytoma (cancer of the astrocyte
cells that biochemically support to the brain’s neurons). It accounts for about 50% of
all brain tumours, with an average patient survival time of around one year even with
surgical intervention, radiotherapy and chemotherapy. Despite this poor prognosis, 36% of patients remain alive after 3 years and are called “long-term survivors”. It might
be expected that this small cohort of long-term survivors would be readily identifiable
in terms of the clinical characteristics of their tumour. However, despite a number of
research efforts, no distinct markers have been found. Pathologists are therefore unable
to reliably predict which patients will be long-term survivors and the mechanisms
behind their long-term survival remain unknown. If the molecular differences between
the tumours from sort-term and long-term survivors could be established, treatment
plans could be better tailored towards individual patients and new drugs to prolong life
could potentially be developed.
In molecular biology, genes encoded in an individual’s genetic blueprint (DNA) are
converted into their functional products (proteins) via an intermediate molecule called
RNA. To date, research aimed at determining gene expression abnormalities has
focussed on analysing DNA or RNA. This project is different in that it focuses at the
level of the functional cellular proteins rather than at the genetic level, asking the
question “what is different in terms of protein expression in tumours obtained from
short-term survivors and long-term survivors of glioblastoma multiforme?”
The protein content of tumour biosamples from short-term and long-term survivors will
be analysed using a technique called “two-dimensional difference gel electrophoresis”.
This involves resolving the protein complement of the tumours into thousands of
distinct spots on A4-sized gels, each spot containing a different protein. The spot
patterns from each biosample are compared and the spots containing differentiallyexpressed proteins highlighted. Although this description of how different the tumours
from short- and long-term survivors are is valuable, the identities of the proteins still
need to be established. This is done by cutting the differentially-expressed spots from
the gels, extracting the protein from them and analysing it by mass spectrometry. Mass
spectrometry determines the amino acid sequence of each protein and this is used to
establish its identity.
By understanding the key biological differences at the protein level between tumours
that kill the patient quickly, and those that do not, we aim to identify key proteins that
could be targeted by either existing or novel drugs, to improve the prognosis for patients
that have a biologically aggressive tumour. Although we accept that this may not result
necessarily in a cure for an individual patient, it has the potential to increase life
expectancy for the group of patients that have the worst prognosis.