SPY1-Mediated Cell Cycle Regulation as a Target to Overcome GSC-induced Therapy Resistance in Glioblastoma

Glioblastoma (GBM) is an extremely lethal type of brain tumour that evades all intricate attempts of modern therapies. Extensive genetic analyses of GBM have indicated a variety of deregulated molecular pathways involved in DNA repair, apoptosis, cell migrationadhesion, and cell cycle regulation. Brain tumour-initiating cells (BTICs) aid in the initiation, progression, and therapy resistance of the heterogenous mass of glioblastoma and are responsible for post-therapy tumour recurrence. BTICs share properties with normal neural stem cells (NSCs), including the ability to self-renew and give rise to differentiated progeny. Previously, our lab established that the levels of an atypical cell cycle protein, SPY1 (RINGO; gene SPDYA) are elevated in malignant human glioma and its upregulation correlates with poor prognosis of patients with GBM. SPY1 is responsible for the symmetric division of BTICs in subsets of high-grade glioma leading to aberrant expansion of those aggressive populations of cells. Spy1 activates Cyclin-Dependent Kinases (CDK) and has been demonstrated to override protective cell cycle checkpoints. We hypothesize that selected targeting of SPY1-CDKs is effective in eliminating BTIC populations and could contribute to more improved therapeutic intervention for subsets of GBM patients in the future. My research project will validate the potential of SPY1-CDK2 targeting for better control over the growth and progression of GBM. The objectives of my study will allow for the evaluation of GBM biology in the face of SPY1 depletion and functional assessment utilizing GBM patient-derived neurosphere cultures and in vivo zebrafish-derived Xenograft (PDX) screening platform.