We have shown that Prazosin, an α-adrenergic receptor antagonist (Kahn et al, 2016 EMBO) and FDA-approved drug for the control of hypertension, induces selective apoptosis of patient-derived glioblastoma (GBM) cells. Prazosin treatment inhibits GBM growth in orthotopic xenograft mouse models and increases survival of GBM-bearing mice, with no toxicity to normal cells (Kahn et al, 2016 EMBO). We have also demonstrated potent activity of Prazosin against Group 3 medulloblastoma progenitors. The potential use of Prazosin in combination with other anticancer immune therapies has not yet been explored.
Immune cells, are critical to the efficacy of many anticancer antibodies. Phagocytic cells, including macrophages, express SIRPα, which binds CD47, a transmembrane protein expressed on all tumors. CD47-mediated activation of SIRPα initiates a signal transduction cascade resulting in inhibition of phagocytosis. We have previously shown that blocking Anti-CD47 antibody enabled phagocytosis of pediatric (Gholamin… Cheshier et al, Science Translational preliminary accepted Jan 2016) and adult (Zhang… Cheshier et al, 2016 PLos One) brain tumors. We also have preliminary data demonstrating additive effects against malignant brain cancer when Prazosin is combined with Anti-CD47.
We hypothesize that the combining Anti-CD47 with Prazosin, will synergistically eliminate medulloblastoma (MB) cells.