Research Projects

Glioblastoma (GBM) is a lethal primary brain tumor that remains a clinical challenge with a median survival of 14 months. To improve patient outcomes, it is crucial to understand signaling mechanisms that give survival advantage to recurrent cells. However, due to the lack of biopsies post-treatment, these mechanisms cannot be studied in patient samples. To bridge this gap, an in vitro cellular model and in vivo orthotopic mouse model were developed from fresh Primary Grade IV GBM tumors and cell lines. Using these models and patient biopsies, it was found that Dual-specificity phosphatase 6 (DUsP6) is significantly upregulated specifically in recurrent GBM. DUsP6 is nuclear localized in GBM cells and inhibits the recruitment of DNAPKcs, apical kinase responsible for DNA double strand break repair via Non-Homologous End Joining (NHEJ). This inhibition results in decreased cell survival and prolonged growth arrest upon irradiation in vitro and increased progression-free survival in orthotopic mouse models of GBM. Dust damage repair (DDR) pathways play a key role in efficient DNA damage repair signaling. This study hypothesizes that a novel non-canonical function of DUsP6 in tweaking phosphorylation of DDR and DNA repair kinetics plays a key role in giving survival advantage to recurrent GBM, making DUsP6 an important therapeutic target. The findings will be validated in clinically relevant patient samples and orthotropic mouse models, providing new mechanistic insights into the DUsP6 mediated function of DNA repair pathway and translationally pertinent information for recurrent GBM therapeutics.