Patients with brain cancers like glioma have a very poor survival rate and although there are various treatment options, there is still no cure for the disease. Better more effective treatments are therefore needed. Current treatment options include: chemotherapy, radiotherapy, immunotherapy, surgery and a variety of drugs. Recent research has allowed a better understanding of the disease, with more specific, targeted treatments being developed. The ATM repair pathway, responds to radiation induced DNA damage, activating a pathway to repair DNA double stranded breaks (DSBs). Small molecule ATM inhibitors were developed in order to prevent the repair of these radiation induced DNA DSBs, in turn preventing the tumour from repairing itself and thus increasing tumour cell death. There have been numerous studies demonstrated the radiosensitisation potential of ATM kinase inhibitors thus suggesting ATM inhibition has great potential as a cancer therapy in combination with radiotherapy. Until recently due to poor solubility ATM kinase inhibitors had not progressed into clinical trials however an orally administered ATM tyrosine kinase inhibitor was recently developed by AstraZenca and patients are being recruited for a phase 1 clinical trial. There are however concerns of potential side effects and it is thought that ATP-competitive ATM inhibitors may cause severe side effects in vivo than a loss of ATM protein expression. Therefore, we aimed to develop a tumour specific delivery system delivering complementary oligonucleotides specific for ATM to silence ATM protein expression. Gold nanoparticles have been shown to not only acquire at the sites of tumours through their leaky, immature vasculature but also enhance the radiosensitisation potential, making the glioma cells more sensitive to radiation. This study will look at the use of gold nanoparticles as a delivery system of ATM inhibition, in order to prevent radiation induced upregulation of ATM as well as assessing the potential radioenhancement by the gold nanoparticles themselves.
|Date of Award
|25 May 2018
- University Of Strathclyde
|Marie Boyd (Supervisor) & Annette Sorensen (Supervisor)