EVALUATING EFFICACY OF REPURPOSED DRUGS IN TREATMENT OF GLIOBLASTOMA

Glioblastoma (GB) is a severe adult brain tumor with a very low median survival time of just ~14 months after surgery and standard of care therapy (Radiation + Temozolomide). Approximately 50% of all GB patients demonstrate amplification of EGFR. However, none of the FDA approved EGFR targeted therapies (Gefitinib and Erlotinib) have shown any efficacy in GB patients due to their restricted blood brain barrier (BBB) permeability. To overcome that challenge, in this study we investigate the efficacy of repurposing two FDA approved drugs, Minocycline and Propranolol, which are also known to cross the BBB, to inhibit EGFR signaling in GB cells. Minocycline is a tetracycline class broad spectrum antibiotic commonly used to treat severe acne and other skin infections; Propranolol is a beta blocker type heart medication primarily used to treat high blood pressure and irregular heartbeat. Based on survey of literature, Minocycline is expected to prevent the phosphorylation of STAT3, a transcription factor downstream of EGFR, while Propranolol is expected to disrupt EGFR trafficking. Efficacy of Minocycline in inhibiting EGFR driven STAT3 activation was investigated using western blot analysis. Our results demonstrate that Minocycline effectively inhibits activation of EGFR driven STAT3 in U373 glioma cells at 100uM. Efficacy of Propranolol in perturbing EGFR trafficking is being evaluated using flow cytometry and immunofluorescence. The effects of these drugs on glioblastoma colony formation are being further evaluated via clonogenic assay. Successful completion of this project will lead to in vivo efficacy testing of Minocycline and Propranolol in glioma PDX models harboring EGFR aberrations.