Targeting the Alternative RNA Splicing Dichotomy of Brain Cancer as a Novel Anticancer Strategy

While known as an adult disease, brain cancers including glioblastoma and diffuse midline glioma are responsible for the the greatest number of deaths of people below the age of 40. I have identified deficiencies in RNA splicing factors in brain cancers, residing in the brain which possesses the highest rate of alternative RNA splicing in the entire human body. The loss of specific splicing factors reduces the overall rate of alternative splicing of master regulators of cell homeostasis and redirects gene expression networks, but also introduces novel splice variants not found anywhere else. Leveraging our preliminary data showing the complete cessation of tumour growth in animal models upon replenishing any one of two RNA splicing factors uniformly lost in glioblastoma, this project will investigate the foundational regulation of these genes and optimise formulation to look at delivering this treatment in a clinical setting. The application of a novel CRISPR-Cas system (Cas12a2) to target cells with unique splice variants will provide another key arm to this program of research for treatment of adult and paediatric brain cancers.