Grant: CIHR Fellowship

Glioblastoma multiforme (GBM) is a lethal brain cancer occurring in both children and adults with a mean overall survival of 14 months. Despite advances in medical technology, diagnosis, and treatment, patient prognosis has only marginally improved. The poor prognosis of GBM is attributed by acquired treatment resistance associated with high levels of genomic instability (GI). DNA damage is common therapeutic approach in many cancers, however current GBM chemotherapies that induce DNA damage has failed to improve patient survival. Interestingly, research in gliomas has demonstrated that GI causes changes in cellular metabolism. Therefore, we hypothesize that a bidirectional relationship between cellular metabolic processes and genomic instability/DNA damage may be involved in acquired resistance and therefore holds potential for a combination therapy approach. We aim to elucidate mechanism that can be exploited to exacerbate DNA damage in GBM tumors and target pathways shared by different clonal populations. With the use of advanced mass spectrophotometry, we will analyze changes in cellular metabolomics caused by DNA damage in GBM cell lines and mouse models. Conversely, we will analyze DNA damage induced by changes in cellular metabolic pathways/oxidative stress response in similar models. These experiments are designed to determine how GI and metabolism communicate and how this communication can be exploited to discover new treatments for GBM patients. Determining reliable targets that can prevent acquired resistance are urgently required to treat this fatal brain cancer.