Targeting circRNA translation in glioblastoma

Project Summary Glioblastomas are highly malignant and invasive, making these neoplasms extremely difficult to surgically resect and these properties often result in tumors which are refractory to standard chemotherapeutic therapies. Unfortunately monotherapies targeting known drivers of glioblastomas such as hyperactive EGFR and c-MET RTKs have proven to be ineffective suggesting redundant mechanisms of activation. We have identified circular RNA-derived proteins which are overexpressed in glioblastoma and these novel products are capable of stimulating receptor tyrosine kinase activity leading to enhanced proliferation, mobility and invasive characteristics. In this application we propose to 1.) determine the mechanism(s) of circ-HGF mediated activation of c-MET in glioblastoma, 2.) clarify the role of PKA/PTBP1 signaling in the regulation of circ-HGF and circ-E-Cad translation initiation and expression in GBM, 3.) evaluate a novel small molecule inhibitor of circ-HGF and circ-E-Cad IRES-dependent translation in orthotopic GBM PDX models. We also propose to investigate and chemically modify the inhibitor to build in desired anti-glioblastoma effects.