The study that we funded as part of our Expanding Theories awards, has identified a gene called serpine1, which is found in the infiltrating cells and not the core cells. They have also seen that a drug targeting serpine1 has promise in slowing, or stopping the infiltration. This early stage research will now need to be backed up with further, more complex testing, but shows progress is happening.
Importance of the Study
Dr Stuart Smith shared the following with us:
"Glioblastoma (GBM) is a highly aggressive brain tumour with an average survival time of only 14 months from diagnosis, despite combined treatment of surgery, chemotherapy and radiotherapy. The identification of new drug targets for GBM is severely hampered by ‘intra-tumour heterogeneity’, a term used to describe differences in biological information within distinct regions of a patient’s tumour. Historically, drug targets for GBM have been predicated on the central, core tumour region which is surgically removed, on the presumption that the biology of this region reflects residual tumour left behind. Current evidence suggests that these residual GBM cells which have infiltrated into the normal brain, likely have different genes switched on or off compared to the GBM core.
"However, attempts to identify genes within infiltrative GBM cells have been complicated by an inability to discriminate between genes from diseased cells and healthy brain cells. A study funded by The Brain Tumour Charity and led by Dr. Stuart Smith (Clinical Associate Professor of Neurosurgery) and Dr. Ruman Rahman (Associate Professor of Molecular Neuro-Oncology) at the University of Nottingham Biodiscovery Institute, has isolated infiltrative GBM cells from normal brain and determined gene patterns unique to this tumour region, which are likely to be associated with re-growth of GBM. Fluorescence guided neurosurgery uses administration of a substance called 5-aminolevulinic acid (5ALA) in a drink taken by patients prior to surgery, generating individually fluorescent tumor cells within a background population of non-fluorescing healthy brain cells. Surgically removed tumour from GBM infiltrative regions was then separated from normal brain cells based on 5ALA fluorescence. The entire set of genes in the human genome from tumour and normal brain was then analysed.
"The work, which has been published in the journal Neuro-Oncology Advances has identified the serpine1 gene as being switched on uniquely in the GBM infiltrative cells. Exposing GBM cells to a drug which inhibits the protein encoded by serpine1, resulted in a reduced capacity of GBM cells to infiltrate. The study offers hope that 5ALA based isolation may become a basis for identifying additional clinically relevant drug targets on infiltrative GBM cells, which more closely reflects the disease which remains in the brains of patients after surgery.